RS55045B1 - Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors - Google Patents

Description

Description of the invention

TECHNICAL FIELD

100011 The invention relates to new bicyclic heterocyclic derivatives of compounds. to pharmaceutical compositions containing the mentioned compounds. as well as on the use of these compounds for the treatment of diseases, cf. cancer.

THE ESSENCE OF THE INVENTION

|0002|According to the first aspect of the invention, a compound of formula (I) was realized:

whereby

—' represents a single or double bond. easily at least one bond in a 5-membered ring system is a double bond;

ring A may be optionally substituted with I. 2 or 3 R'<1> groups:

B represents a -heterocyclyl group, wherein said heterocyclyl group may be optionally substituted with 1,2 or 3 R'<1> groups;

R<a>represents halogen. C,.„ alktl. C:.„ alkenyl, C\„(, alkynyl, C\.scykioaIki 1. C;.s cycloalkenyl, -OR\ -0-(CH;.)„-OR\ haloC,,,, alkyl. haloC,.,, alkoxy, CM) alkanol. =0. =S. nitro. Si(R<x>)4. -(Cl -IA-CN. -S-R\ -SO-R\ -SO.-R\ - COR\ -(CR<v>R<y>)rCOOR'. - (CH,)s-CONRvR\ -(CH^-NR^. -(CH»),-NRvSO:-R\ -(CH,),-Nll SO.-NirR .-(X ()NRM<\ (l H•). \RV()-R\ -O-iCH ), i' RIV (CIU-OR j|i -((11 ).-SO-\R"R% groups; R<x>, R<y>and R* independently represent hydrogen, C,.r, alkyl, C>_,, alkenyl, (',.„ alkynyl, CM> alkanol. hydroxy.C,. « lkoxy, haloC,.,, alkyl, -CO-(CH2)"Ci-(> lkoxy. C;.scycloalkyl or CYS cycloalkenyl;

R<7> and R<*> independently represent hydrogen, C,.(, alkyl, C...„ alkenyl, C..f, alkynyl. Ci.scycloalkyl. C.;«cycloalkenyl, aryl. heterocyclyl or R' and R<*> together with the nitrogen atom to which they are attached may form a heterocyclyl ring containing nitrogen. wherein said C,.„ alkyl. aryl and heterocyclyl may be optionally substituted with 1, 2 or 3 R<1>' groups;

R' and R<b>independently represent the R" group or -Y-carbocyclic or -Z-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups can be optionally substituted with 1, 2 or 3 R:| groups;

Y and Z independently represent a relationship. -CO-<C!R- -COO-. (CI U),,-. -NRX-(C! IA-. -<CH,)S--NRX-, -CONR\ -

NRTO-. SO -NR<x>SO?-, -NR'CONl<V->, -NRVSNK-.

• O-K'H ),-. -(Cl-K),-0-. -S-. -SO- or <CI|.) •>().-.

n represents an integer from 1-4:

s and t independently represent an integer from 0-4;

q represents an integer from 0-2:

or a pharmaceutically acceptable salt or salt thereof.

|0003| The compound of formula (1") is described:

whereby

each X,. X: and X; is independently selected from carbon or nitrogen. so that at least one of X,-X;represents nitrogen and so that when X| represents nitrogen. then at least one of X<. X,. X, and X*nitrogen:

X., represents CR<5>. nitrogen. NH or C (>:

X, represents CR". nitrogen, NH or C-O:

u/, us lov that more than three XrXs do not represent nitrogen:

»—' represents a single or double bond. such that at least one bond in the 5-membered ring system is a double bond and such that the bond between X.( and X< represents a single bond when X4 or Xs represents C=-0;

R' represents hydrogen. halogen, C,„ alkyl, C\„ alkenyl. C,„ alkynyl. C, " alkoxy, C)rflcycloalkyl, C.u. cycloalkenyl. cyano. haloC,.<, alkyl or haloC\,, alkoxy: A represents an aromatic or non-aromatic carbocyclic or heterocyclic group which may be optionally substituted with one or more (e.g. 1,2 or 3) R" group: B represents -V-carbocyclic group or -Vv'-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) R" groups;

R* represents halogen, hydrogen. CM, alkyl. Cm. Alkoxy. C1 alkenyl. with one or more R" groups;

R<c>. R<1> and R" independently represent hydrogen or Cu> alkyl:

R" represents halogen. CN, alkyl. CY„ alkenyl. C,.„ alkynyl. (:,.„ cycloalkyl, C;.„ cycloalkenyl. -OR<v>. -0-(CH.)„-OR\ haloC,.«, alkyl. haloC,.«. alkoxy. C,,, alkanol. O. S. nilro. Si(R"),. -(CIM,-CN. -S-IC. -SO-R\ -SO-R\ -

COR\ -(CR'R-)„-COOR'. -(CH-,),-

-CONR<*>R<y>. -(CHA-NRV. -(CHA-NRXT>R\ -i.CII?K-NR<x>SO..-R\ -(Cl I O.-NI l-SO-NR"R\ -OCONR"R>. -(CH,),-NR\:0:R\ -0-(CT:.k-n<Mr-<( Ha-OR ' or -(CH .),-SO-NR'R\) groups: R\ R" and R' independently represent hydrogen, C,„ alkyl. (."..„ alkenyl. C\„ alkynyl, CM, alkanol. hydroxt. C,.„ alkoxy, haloCu, alkyl. -CO-(CHO„-C'i-(. alkoxy. C' :.s cycloalkyl or C.s cycloalkenyl;

K<2>represents -CONR<;>R<s>. -COR<x>or ( OOR group:

R and Rs independently represent hydrogen, C,.,, alkyl, ( '•„ alkenyl. ('.„ alkynyl. C*s.s cycloalkyl. CV* cycloalkenyl. aryl. heterocyclyl or R and R* together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclyl ring, wherein said C|.,, alkyl. aryl and heterocyclyl may be optionally substituted with one or more (e.g. 1. 2 or 3) Rb group: R<1> and R<1>' independently represent an R<1>' group or a -Y-carbocyclic or -/-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups can be optionally substituted with one or more (eg 1.2 or 3) R" groups;

V and W independently represent a bond or -(CR'R'^-group;

Y and Z independently represent a bond, (()-((!!-!-. -COO-. -(Cl I ,)>.-. N K (C 11 -)... - (CH,)t-NR\ -CONR\ - NIVCO-, -SO>NR\ -NRsSOr. -NR'CONR-, -NRTSNR'<1->. -0-(Cl l•),-. -(('11,)_-(..)-. S-). -SO- or -(CTLVSO-.-: n represents an integer from 1-4;

s and i independently represent an integer from 0-4:

q represents an integer from 0-2:

or a pharmaceutically acceptable salt thereof. solvate or derivative.

|(10041WO 01'38326 (Merck). VVO 200.3 048 132 (Merck). WO 02 0X0014 ((.rucnenthal). VVO 0114375 (Astra Zeueca). VVO 2004/052286 (Merck). VVO 00 53605 (Merck). VVO 03 101993 (Neouenesis).VVO 2005/054230 (Cvtopiu).VVO 0M66098 (VVarner Lambert). (Sirtris Pharmaceuticals) and US 2006/0035921 (OSI Pharmaceuticals) each describes a series of heterocyclic derivatives.

10005|EP 1 790 650 (Banvu Pharma) describes substituted imidazole derivatives and a PI.KI inhibitor or anticancer agent containing the same.

|0006|In VVO03/09981 I (Cvtopia) compounds are described which are based on a disubstituted pyran/ine skeleton which are inhibitors of protein kinases.

|0007|VVO2005/021531 (OSI Pharma) describes N-substituted benzimidazolyl compounds that are c-Kit pro-oncogene inhibitors.

|0008] In VVOOO 53605 (Merck) inhibiting compounds are described. regulate and or modulate tyrosine kinase signal transduction. compositions containing these compounds. and methods of receiving them for the treatment of tyrosine kinase-dependent diseases and delivery.

10009 [In VVO2008/07809I (Astex) compounds are described - bicyclic heteiocyclic derivatives and the use of said compounds in the treatment of diseases such as cancer.

DETAILED DESCRIPTION OF THE INVENTION

100101According to the first aspect of the invention, the compound of formula (I) was realized:

whereby

—-- represents a single or double bond. thus at least one bond in the 5-membered ring system is a double bond;

ring A may be optionally substituted with 1, 2 or 3 R:' groups;

B represents a -heterocyclyl group, wherein said heterocyclyl group can be optionally substituted with 1, 2 or 3 R" groups: R" represents halogen. C,.,, alkyl. C- >. x alkenyl. C... alkynyl. C-. -(CR<X>R<>>VCOOR'. - (C'H:),-CONR<v>R\-(ClI^-NR^. -<CII .),-NRxCORs. -(CM<),-NR<x>SO>-R-\ -(CH,)„-NI4-SO,-NRxR\ -OCONRxR\ -(CH2),-NRxCO.;R>. -O-(CH,K-CRxR,-(CH.),-0R/ or -(CH.)»-SO,NR'<t>R<>>groups: R\ Ry and R' independently represent hydrogen. C|.„ alkyl. C...,, alkenyl. C\.„ alkynyl. C,.(, alkanol, hydroxy. C,.,, alkoxy, haloC,,,, alkyl. -CO-(CH:. )„-(?,.„ alkoxy. (",.„ cycloalkyl or Cj.scycloalkenyl: R and R<s>independently represent hydrogen. Cu„ alkyl. C-.„ alkenyl. ('•.,. alkynyl. C:.. s cycloalkyl, C\. s cycloalkenyl. aryl. heterocyclyl or R and R<*> together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclyl ring, wherein said C 1.<. alkyl, aryl and heterocyclyl may be optionally substituted with I. 2 or 3 Rh groups;

R<1> and Rh independently represent an R" group or -Y'-carbocyclic or -/-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups can be optionally substituted with I. 2 or 3 R<1>' groups: Y and Z independently represent a bond, -CO-(CH..),-. -COO-. -(Cll,),,-. -NR<X->(CH-)S-. -(CH.-k-NRV -CONR<x->, - NRxCO-, -SO,NRx-, -NR<x>SO;.-. -NR<x>CONir-, - ()-(CI 1 ,},-. -(CH-k-O- -S-. -SO- or -(CH.K-SO-

n represents an integer from 1-4:

s and t independently represent an integer from 0-4:

q represents an integer from 0-2;

or a pharmaceutically acceptable salt or solvate thereof.

100111 The compound of formula (I") is described:

whereby

each X,, X, and X? is independently chosen between carbon or nitrogen. although at least one of X,-X; represents nitrogen and so that when X, represents nitrogen. then at least one of X>X ;. X , and X< nitrogen;

X, represents CR\ nitrogen. NH or OO;

X. represents CR". nitrogen. NM or (' <>.

with the proviso that more than three XrX< do not represent nitrogen; —— represents a single or double bond. thus at least one bond in the 5-membered ring system is a double bond although the bond between X, and X< is a single bond only when X4 or X< is CO;

R"' represents hydrogen. Halogen, C,.„ alkyl. C,,, alkenyl. ('..,, alkynyl.(',.,, alkoxy.C, "cycloalkyl. C?.,, cycloalkenyl. cyano. haloC|.„ alkyl or haloC,.,, alkoxy;

A represents an aromatic or non-amatic carbocyclic or heterocyclic group which may be optionally substituted with one or more (eg 1, 2 or 3) R" groups;

B represents -V-carbocyclic group or -\V-heterocycles! a group wherein said carbocyclic and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) R" groups;

R" represents halogen. hydrogen, C,.„ alkyl. C|.„ alkoxy. ( . alkenyl. (">(1 alkynyl. - C N. C? cycloalkyl. C\scycloalkenyl. -NHSO.-R", -CH~N-OR". or a 3-6-membered utonocyclic helerocyclyl group, wherein the mentioned Cu, alkyl. Cj.Aalkenyl, (\.„ alkynyl, C|,„ alkoxy and heterocyclyl groups may be optionally substituted with one or more R" groups;

R<l>. R1 and R<w>independently represent hydrogen or C1, alkyl;

R" represents halogen. C,.„ alkyl. C.M, alkenyl. (\„ alkynyl. C .scycloalkyl. ('? cycloalkenyl. -OR\ -0-(CH>)n-OR\ haloC,.,, alkyl. haloCj.,, alkoxy. C,.f>alkanol. 0. S. nitro. SiMC).,. -(Cl l-k-CN. -S-R\ -SO-R\ -SO:-R\ -

COR\ -(CR'R<y>),-COOR'. -(CH,),-CONR<x>R;. -(CH.,),-NRNR\ -<l H ),-NRX OR-. -(CH:).-NR<v>SOrR<>>. -(CH3),-NHSQ>-NRXR\ -OCONRsR\ -(CH,),-NRvC07R\ -0-(CH/»S-C'RXR''-(CI |.»,-()R' or -fCHA-SO-NiriV groups: R\R-and R' independently represent hydrogen. C, „ alkyl. C\(, alkenyl. ('■.„ alkynyl. *,.„ alkanol. hydroxy. CM, , alkyl, -CO-(CH)-Cu, , , , , , , , , , , , , , , , , , , , , , , , , , , ,

R' and R<8> independently represent hydrogen. C,.,, alkyl. C..„ alkenyl. C'-.„ alkynyl, C ,K cycloalkyl, C-.. x cycloalkenyl. aryl. heterocyclyl or R<7> and Rx together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclyl ring, wherein said C,.,, alkyl. aryl and heterocyclyl may be optionally substituted with one or more (e.g. 1.2 or 3) Rh group: R1 and R1' independently represent a Ra group or a -V-carbocyclic or -Z-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups can be optionally substituted with one or more (e.g. I. 2 or 3) R:1 groups:

V and VV independently represent a bond or -(CR'R<1>),,-group:

Y and Z independently represent a bond. -CO-(CH >).-. -COO-. -iCH.),,-. -NRMCH;)S-. - (CH>),-NR\ -C0NR"-, - NRTO-. -SOjNRV -NR^SOr- -NRT0NR--. -NRTSNR>-. -0-(CH,>„-. -(CHA-O-. -S-. -SO- or -(CH^-SO,-: n represents an integer from 1-4);

s and t independently represent an integer from 0-4:

q represents an integer from 0-2;

or a pharmaceutically acceptable salt thereof. solvate or derivative.

100121 The compound of formula (Ta) is described:

whereby

each X|. X. and X; is independently chosen between carbon or nitrogen. provided that at least one of XrX; represents nitrogen: X.i represents CR' or nitrogen;

X5 represents CR". nitrogen or C=0;

with the condition that more than three X,- X< do not represent nitrogen:

represents a single or double bond. so that when Xrepresents C(). then X, and X*, are connected by a single bond and thus at least one bond in the 5-membered ring system is a double bond: R' represents hydrogen, halogen, C|.„ alkyl. C:.„ alkenyl. A represents an aromatic or non-aromatic carbocyclic or heterocyclic group which may be optionally substituted with one or more (e.g. 1. 2 or 3) R<il> group: B represents a -V-carbocyclic group or -VV-heterocyclyl group, whereby the said carbocyclic and heterocyclyl groups may be optionally substituted with one or more (e.g. 1. 2 or 3) R:<i>group;

R" represents halogen. hydrogen. C,.<, alkyl. CN. alkoxy. C\.„ alkenyl. ('.„ alkynyl. - C~N. C;.* cycloalkyl, Cj.«cycloalkenyl. -NHSO.R". -CH=N-OR<l>\ or a 3-6-membered monocyclic heterocyclyl group, wherein the mentioned CM, alkyl. alkenyl. C7... alkynyl. Cu, alkoxy and heterocyclyl groups may be optionally substituted with one or more R" groups;

R<*>. R' and R" independently represent hydrogen or C1..,. alkyl:

R" represents halogen, C,.,, alkyl. C7.„ alkenyl. C\„ alkynyl. Ci.s cycloalkyl, C-,.scycloalkenyl, -OR\ -O-(CI-U),,-OR\ haloC,.,, alkyl. haloC,.,, alkoxy. Cu, alkanol. =0. =S. nitro. Si(R<v>),. -(CH7),-CN. -S-R\ -S0-R\ -S07-R\ - ĆORA -(CR<x>R,)s-COOR'. -(CH;k-NRxRv. -(CH,).-NRTOR>. -{Cll7)s-NR<x>SO:-R<y>. -<CH,)S-NHSO-NRxR\ -OCONirR- , -<CH7.v,-NRvC07R'. -O-(C11^),-('Rx R'-(CM ■ ),-0R' or -(CH7)s-SO,.N<Rx>R<y>groups: R\ Ry and R' independently represent hydrogen. C*M, alkyl. C»„ alkenyl. C„.,„ alkynyl. CM. alkanol, hydroxy. C,.«, alkoxy. haloC,.,, alkyl. -O )-i ( 11.),-(',Alkoxy.C" cycloalkyl or C-.s cycloalkenyl:

R2 represents -CONR7Rs. -CORx or -COOR' group:

R and R<*> independently represent hydrogen, C|.„ alkyl. CM, alkenyl. C " alkynyl, C\.« cycloalkyl. (' ..: cycloalkenyl. aryl. heterocyclyl or R<7> and R<*> together with the nitrogen atom to which they are attached may form a heterocyclyl ring containing nitrogen. wherein said alkyl. aryl and heterocyclyl may be optionally substituted with one or more

(e.g. 1.2 or 3) R1' group:

R<1> and Rb independently represent the R*' group or -Y-aryl or -/-heterocyclyl group, wherein said aryl and heterocyclyl groups may be optionally substituted with one or more (eg 1, 2 or 3) R'<1> groups;

V and W independently represent a bond or -(CR'R'^-group:

Y and 7 independently represent a bond. -CO-(CH7),-. -COO-. -(CH.

n represents an integer from 1-4:

s and t independently represent an integer from 0-4:

q represents an integer from 0-2:

aryl represents a carbocyclic ring:

heterocyclyl represents a heterocyclic ring,

or a pharmaceutically acceptable salt, solvate or derivative thereof.

100131 The compound of formula (l'b) is described:

whereby

each X|. X7 and X; is independently chosen between carbon or nitrogen. so that at least one of X,-X!represents nitrogen and so that when X| represents nitrogen. then at least one of X-. X;. X , and X> nitrogen;

X4 represents CR' or nitrogen;

X5 represents CR6, nitrogen or C=0; with the proviso that more than three XrX< do not represent nitrogen; • represents a single or double bond. so that at least one bond in the 5-membered ring system is a double bond;

R' represents hydrogen, halogen. C|.„ alkyl. C,..„ alkenyl. C'7.„ alkynyl.CM> alkoxy, C«, cycloalkyl, C>.„ cycloalkenyl. cyano, haloC|.(, alkyl, haloC|„ alkoxy or "O:

A represents an aromatic or aromatic carbocyclic or heterocyclic group which may be optionally substituted with one or more (eg 1,2 or 5) R:| group: B represents a -V-carbocyclic group or -W-heterocyclyl group wherein said carbocyclic and heterocyclyl groups can be optionally substituted with one or more (e.g. I. 2 or 3) R' group: R" represents halogen. hydrogen, (',,,, alkyl. C,. alkoxy. C\„ alkenyl. C...,, alkynyl. - C N. Cv* cycloalkyl. ("-,.* cycloalkenyl. -NHS04V\ -(.'II S-OR". or a 3-6-membered rionocyclic heterocyclyl group, wherein said CM,

alkyl, C1-6, alkenyl. C 1 - alkynyl, C 1 - alkoxy and heterocyclyl groups may be optionally substituted with one or more

"R" group:

R\ R<1> and R" independently represent hydrogen or C 1-4 alkyl;

R" represents halogen, CM, alkyl, C..„ alkenyl. (">.„ alkynyl. C .s cycloalkyl, ( cycloalkenyl. -OR\ -0-(CH.->)„-OR\ InloC,. alkyl. h.a'.oC .. alkoxy. C,.„ alkanol. (>. S. nitro. Si(R<x>},, -i( II i. C\. -S-K\ -SO-R\ SO-R.

COR\ -(CR<X>R<X>),-COOR'. -(CH.,),-CONR<x>R\ -(CH<K-NR"R\ -(Cl I -I..-N R %COR\ -(Cl NS-NRXS()-R\ -(CH,),-NHSO>-NR<x>R-, -OCONRxR\ -(CM.). NR'CO.R . -()-.( II.i CRR »Cl I !-OR or -(ClR-SONRM<*>groups;

R\ R<>> and R' independently represent hydrogen. Calcyl. CMl alkenyl. C...„ alkynyl. C1.„ alkanol. hydroxy. C1.,, alkoxy. haloCM, alkyl, -CO-(CH;),rC,.<, alkoxy, C;.s cycloalkyl or C;.scycloalkenyl:

R" represents the -CONrV. -COR" or -COOR' group:

R' and R<*> independently represent hydrogen. C<*>M, alkyl. Cm. alkenyl. Alkynyl.C-..*cycloalkyl. C1.cycloalkenyl, aryl. heterocyclyl or R and Rk together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclyl ring. wherein said alkyl. aryl and heterocyclyl may be optionally substituted with one or more (eg 1, 2 or 3) R 1' groups;

R<1> and R<1>' independently represent the R'<1> group or -Y- carbocyclylene or -Z-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups may be optionally substituted with one or more (eg I. 2 or 3) R'<1> groups:

V and W independently represent a bond or -<CRT\<!>),,-group:

Y and Z independently represent a relationship. OMCII). -COO-. -(CII.),,-. -NR<X->(CH<)"-. - (CTI;)"-NR<X->. -CONR" . -NRxCO-, -SO,NRx-, -NRxSO>-, -NRxCONR--. -NRXCSNRX-, -0-<CrR-, -(CIR-O. -S-. -SO- or -(CH:k-SO:-:

n represents an integer from 1-4:

s and t independently represent an integer from 0-4:

q represents an integer from 0-2:

or a pharmaceutically acceptable salt thereof. solvent or derivative.

|00I4| When used herein for a group or part of a group, the term <*>Ct." alkyl" refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopemyl, neopentyl or hexyl, and the like.

100151 When used herein for a group or part of a group, the term "CM, alkenyl" refers to a linear or branched hydrocarbon group containing an OC bond.

|0OI6|When used here. the term "C 1 , , , , , , , , , alkyl group, wherein C , , , alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, and the like.

|00I7| As used herein, the term '(",.„ alkanol') refers to a C7" alkyl group substituted with one or more

of hydroxyl Lnjupn, whereby C i_r, tilkyl ontiktiv ktio si ic here defined. Examples of such expressions include hydroxymethyl hydroxyethyl, hydroxypropyl and the like.

10018| As used herein, the term "C 1-6 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having from 1 to 8 carbon atoms. Examples of such groups include cyclopropyl. cyclooctnyl. cyclopentyl. cyclohexyl. cycloheptyl or cyclooctyl and the like.

|0019) As used herein, the term 'C-(1cycloalkyl') refers to a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

|0020| As used herein, the term 'halogen' refers to a fluorine atom. chlorine. bromine or iodine.

|0021| As used herein, the term "haloC1.,, alkyl<*>refers to a C1,.,, alkyl group as defined herein. wherein at least one hydrogen atom is replaced by a halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.

100221 Kada se ovde koristi, izraz 'haloC,.,, alkoksi' se odnosi na C".,. alkoksi grupu onakvu kao što je ovde detlnisana, pri čemu je najmanje jedan atom vodonika zamenjen sa halogenom. Primeri takvih grupa obuhvataju difluorometoksi ili irifluoromeioksi i slično,

When used herein, reference to "carbocyclic" and "lieterocyclic" groups includes, unless the context indicates otherwise, both aromatic and non-aromatic ring systems. Accordingly. for example. the term "carbocyclic and heterocyclic groups" includes aromatic, non-aromatic groups. unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. In general, such "holes" can be non-monocyclic or bicyclic and can contain, for example. 3 to 12 ring members, more commonly 5 to 10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, more commonly 3 to 7, and preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8. «. Cl. Both 1 and 12 ring members, more commonly 9 or 10 ring members. When carbocyclic and heterocyclic groups are referred to herein, then a carbocyclic or heterocyclic ring may be. unless the context otherwise indicates, unsubstituted or substituted with one or more substituents, for example. molecular fragments, molecular skeletons or functional groups discussed herein. References to "carbocyclic" and "lieterocyclic" groups are understood to include references to carbocyclic and heterocyclic groups which may be optionally substituted with one or more (eg 1, 2 or 3) R' or R1' groups.

|0024| Carbocyclic or heterocyclic groups may be aryl or heteroaryl groups having from 5 to 12 ring members, more usually from 5 to 10 ring members. As used herein, the term "aryl" refers to a carbocyclic group having aromatic character, and the term "heteroaryl" is also used herein to refer to a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl" include polycyclic (eg, bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group can be attached to an aromatic ring, or to a non-aroniatic ring. The term "aryl" is intended to have the meaning defined herein except for compounds of formula (Ia). (Ic) and (cl), wherein the aryl is a carbocyclic ring as defined herein. In one embodiment of the compound of formula (la). (Ic) and (Id). aryl represents an aromatic ring.

100251 The term "non-aromatic group" includes unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure or structures contain atoms that

share more than one valence bond ij. the ring contains at least one multiple bond e.g. (***"(*. ('=(.' or N=C bond. Expression

"fully saturated" refers to rings where there are no multiple bonds between the ring atoms. Saturated carbocyclic groups include cycloalkyl groups as delineated below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below. for example. cyclopenenyl.

cyclohexenyl, cycloheptenyl and cyclooctenyl. Saturated heterocyclic »holes include piperidine. morpholine. thiomorpholine. Partially saturated heterocyclic groups include pyrazolines. for example. 2-pyrazoline and 3-pyrazoline.

100261 Examples of heteroaryl groups are monocyclic and bicyclic groups containing from pel to twelve ring members, more commonly from pel to ten ring members. A heteroaryl group can be for example. a five-membered or six-membered monocyclic ring or a bicyclic structure formed by fused five- and six-membered rings or two fused six-membered rings, or two fused five-membered rings. Each ring can contain up to about five heteroatoms. usually chosen between nitrogen. sulfur and oxygen. Typically a heteroaryl ring will contain up to 4 heteroatoms. more commonly up to 3 heteroatoms. even more commonly up to 2, for example. only one heteroatom. In one exemplary embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of imidazole or pyrithin. or essentially non-core. as in the case of nitrogen in indole or pyrrole. Generally, the number of basic a/ot atoms present in the heteroaryl group, including any ring amino group substituents, will be less than five.

|0027| Examples of five-membered heteroaryl groups include. but are not limited to pyrrole. turane, thiophene. imidazole. furazan, oxazole. oxadiazole, oxatriazole. isoxazole. thiazole. thiadiazole, isothiazole. pyrazole. triazole and tetrazole groups. Another example of a five-membered heteroaryl group includes thiadiazole,

100281 Examples of six-membered heteroaryl groups include. but are not limited to pyridine, pyrazine, pyriclazine. pyramid and

Iriazin.

|0029| A bicyclic heteroaryl group can be for example. a group selected from the following:

a) benzene ring condensed on a 5- or 6-membered ring containing I. 2 or 3 heteroatoms in the ring:

b) pyridine ring condensed on a 5- or 6-membered ring containing I. 2 or 3 heteroatoms in the ring: cl pyrimidine ring condensed on a 5- or 6-membered ring containing I or 2 heteroaloniums in the ring; d) a pyrrole ring condensed on a š- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

e) pyrazole ring condensed on a .v or 6-membered ring containing 1 or 2 heteroatoms in the ring:

f) imidazole ring condensed with a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring:

d) oxazole ring condensed on a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring:

h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 hydrogen atoms in the ring;

ijthiazole ring fused to a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring:

j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring;

k) thiophene ring condensed on a 5- or 6-membered ring containing I. 2 or 3 heteroatoms in the ring:

I) a furan ring condensed on a 5- or 6-membered ring containing I. 2 or 3 heteroatoms in the ring; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1. 2 or 3 ring heteroatoms: and n) a cyclopentyl ring fused to a > or 6-membered ring containing I. 2 or 3 ring heteroatoms. |0030| Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another six-membered ring include, but are not limited to imidazolinazole (e.g., imidiazo]2,1-bithiazole) and imidiazolimidazole (e.g., imiidazo 1,2-a|imidazole). beiizol'uran. ben/othiolene. henzimidazole. benzoxazole. isobenzoxazole, benzisoxazole. benzthiazole. benzisothiazole. isobenzofuran, indole. isoindiol. indolizine. indoline. isoindoline. purine (eg adenine. guanine), indiazole. pyrazolopyrimidine (e.g., pyrazolof 1.5-a|pyrimidine), (riazolopyrimidine (e.g., [ l,2.4]triazolo| l.5-a|pyrimidine>. benzodioxole. imidazopyridine and pyrazolopyridine (e.g., pyrazolo' l.5-a|pyridine) groups).100321 Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to chromane, benzodiazine, quinazoline, and aryl groups. includes tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydrochino lithi. dihydrobenzthien. dihydrobeuzfuran. 2.3-dihydro-benzo(1,4)dioxin. benzo[ 1.3 |dioxol. 4.5.6,7-tetrahydrobenzoturates. tetrahydrotriazolopyrazine (eg 5.6.7.8-tetrahydro-f l,2.4|triazolo[4.3-a]pyrazine).indoline and indate groups.|0034|The nitrogen-containing heteroaryl ring must contain at least one nitrogen atom in the ring. In addition. each ring may contain up to about four other heteroatoms usually selected from nitrogen. sulfur and oxygen. Typically a heteroaryl ring will contain up to 3 heteroatoms. for example. t. 2 or 3. more commonly up to 2 nitrogens. for example. only one nitrogen. The nitrogen atoms in heteroaryl rings can be basic, as in the case of imidol or pyridine. or essentially non-basic. as in the case of nitrogen in indole or pyrrole. Generally, the number of base nitrogen atoms present in a heteroaryl group, including any ring substituent amino groups, will be less than five.100351 Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl. pyrrolyl, imidazolyl. oxazolyl, oxadiazolyl. thiadiazolyl. oxatriazolyl, isoxazolyl. thiaz.olyl. isothiazolyl. furazanil. pyrazolyl. pyrazinyl. pyrimidinyl, pyridazinyl, triazinyl. triazolyl (eg 1.2.3-lriazolyl. 1.2, l-triaz.olyl).letrazolyl. li ino) ini i. isoquinolinyl. benzinidazolyl. benzoxazolyl. benzisoxazole. benzthiazolyl and benzthiazolyl. indjolil. 311-indjolyl. isoindolyl. indolizinyl. isoindolinyl, purines I (eg adenine [6-aminopurine], guanine (2-amino-6-hydroxypurine \). iadazolyl. quinolizinyl. benzoxazinyl, benzodiazinyl. pyridopyridinyl. quinoxalinyl. Iinazolinyl. quinolinyl. ilaiaziniI. naphthyridinyl and pteridinyl.100361 Examples of nitrogen-containing polycyclic heteroaryl groups. and containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl. letrachydroquinolinyl and indolinyl. [00371 Examples of carbocyclic aryl groups include phenyl, naphthyl. indenyl. and tetrahydronaphthyl groups, Examples of non-aromatic heterocyclic groups are groups having from 3 to 12 ring members, more commonly from 5 to 10 ring members. Such groups can be monocyclic or bicyclic. for example. and usually have from 1 to 5 heteroatoms as ring members (more commonly I. 2. 3 or 4 heteroatoms as ring members), usually chosen from nitrogen. oxygen and sulfur. Heterocyclic groups may contain, for example. cyclic ether groups (e.g. as in tetrahydrofuran and dioxane), cyclic thioether groups (e.g. as in tetrahydrothiolene and cyanide). cyclic amino groups (eg as in pyrrolidine). cyclic amide groups (eg as in pyrrolidion). cyclic thioamides. cyclic thioesters. cyclic ureas (eg as in imidazolidin-2-one) cyclic ester groups (eg as in butyrolactone). cyclic sulfones (eg, as in sulfolane and sulfolene). cyclic sultboxides. cyclic stylphonainides and their combinations (eg liomorpholine).|0039|Special examples include morphblin. piperidine (eg 1-piperidinyl. 2-piperidinyl. 3-piperidinyl and 4-piperidinyl). piperidone, pyrrolidine (eg 1-pyrrolidinyl. 2-pyrrolidinyl and 3-pyrrolidinyl). pyrrolidone. azetidine. pyran (21 l-pyran or 411-pyran), dihydrothiotene, dihydropyran. dihydrofuran. dihydroyiazole. tetrahydroruraii. letrahydrolyolene. gyoxau. tetrahydropyran (eg 4-tetrahydropyranyl). iniidazoline. imidazolidinone. oxazoline. thiazoline. 2-pyrazoline. pyrazolidine, piperazone. piperazine, and N-alkyl piperazines, such as N-methyl piperazine. In general, preferred non-aromatic heterocyclic groups include saturated groups, such as piperidine, pyrrolidine. azetidine. morphblin. piperazine and N-alkyl piperazines.100401In a non-aromatic nitrogen-containing heterocyclic ring. the ring must contain at least one nitrogen atom in the ring, and heterocyclic groups can contained, for example. cyclic amino groups (eg as in pyrrolidine). cyclic amides (as in pyrrolidinone, piperidone or caprolactam). cyclic sulfonamides (such as isoliazolidine 1.1-dioxide. [ 1,2]thiazinan 1.1-dioxide or 11.2 jthiazepane 1.1-dioxide) and their combinations. Specific examples of non-aromatic nitrogen-containing heterocyclic groups include aziridine. mortblin. thiomorpholine. piperidine (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl). pyrrolidine (eg 1-pyrrolidinyl. 2-pyrrolidinyl and 3-pyrrolidinyl). pyrrolidone, dihydrothiazole. imidazoline. imidazolidinone. oxa/olin.liazolin. ol 1-1,2.5-thiadiaziu. 2-pyrazoline. 3-pyrazoline. pyrazolidine. piperazine. and N-alkyl piperazines. such as N-niethyl piperazine.|00411 Carbocyclic and heterocyclic groups can be polyethylen cordon/ram and ring systems or bridged ring systems, such as bicycloalkanes. tricycloalkam and their oxa- and aza analogues (eg adamantane and oxa-adamantane). For an explanation of the difference between fused and bridged ring systems, see Advanced Organic Chemistry. by Jerry March. 4th edition. Wiley Interscience. sirane 13 I-133. I°Q2. Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl. cycloalkenyl groups such as cyclopentenyl, cyclohexenyl. cycloheptenyl and cyclooctenyl. as well as cyclohexadiene. Eycloclatetraene. tetrahydronartenyl and decalinyl.100421 Any heterocyclic group can be unsubstituted or substituted with one or more substituent groups. For example. heterocyclic groups can be unsubstituted or substituted with I, 2, 3 or 4 substituents. Where the heterocyclic group is monocyclic or bicyclic. it is usually unsubstituted or has 1, 2 or 3 substituents. 100431 Examples of ring systems covered by the definitions of X,-X, are shown in the following formulas (a)-(p) and (r)-(t): |0044|The following examples of ring systems covered by the definitions of XrX< are shown in the following formulas (u)-(v):

|0045|As stated above. " represents a single or double bond. One skilled in the relevant art will appreciate that when X, or X< represents C O. then X, and X< are linked by a single bond. And ! in one embodiment X,| and X< are linked by a double bond.

10046]In one exemplary embodiment, the two bonds in the 5-membered ring system are double bonds.

[0047|A compound is described in which X| represents C.

100481 A compound is described in which X, and X-, represent C, X< represents CH and X> and X( represent nitrogen (ie, the ring system of formula (a)).

100491A compound is described in which X, and X; represent C. X., and X. represent CH and X. represent nitrogen (ie, the ring system of formula (e)).

100501 A compound is described in which X| and X; represent ('. X4 represents CH and X- and X< represent nitrogen (ie the ring system of formula (0).

|005l|A compound is described in which X, and X. represent C. X; represents nitrogen. X( represents CR' (eg, CH) and X5 represents CR<*> (eg, C-Me) (ie, an example of a ring system of formula (h)).

100521 In one exemplary embodiment, X, and X.. represent O. X, and X, represent CH and X: represents nitrogen (i.e.

example of a ring system of formula (j)).

|0053|A compound is described in which X, and X.- represent C. X., represents CH and X and X^ represent nitrogen (ie, an example of a ring system of formula (k)).

10054jA compound is described in which X- and X: represent C. X, represents CM and X, and X, represent nitrogen (ie, an example of a ring system of formula (r)).

10055|A compound is described in which X,. X and X > represent C and X. and X represent nitrogen (ie, an example of a ring system of formula (a)).

|0056|A compound is described in which X,. X;. X! and X* represent C and X > represents nitrogen (ie, an example of a ring system of formula(s)).

|00571A compound is described in which X|. X- and X| represent C and X. and X*represent nitrogen (ie, an example of a ring system of formula (f)).

100S81 A compound is described in which X, and X > represent C. X ; I introduced nitrogen. X represents CR' (eg CH) and X; represents CR" (eg, C-Me) (ie, an example of a ring system of formula (li)).

100591 In a variant embodiment. X | X> X4 and X< represent C and X-. represents nitrogen (ie, an example of a ring system of formula (j)).

100601A compound is described in which X|. X> and X, represent C and X-, and \< represent nitrogen (ie, an example of a ring system of formula (k)).

|0061|A compound is described in which X>. X; and X represent C and X, and X represent azole (Ij. example of a ring system of formula (r)).

100621 The compound in which X represents C is described.

100631A compound is described in which X; represents N.

|0064|A compound is described in which X.trepresents (II or CR.

|0065|A compound is described in which X5 represents CH or CR".

|0066]A compound is described in which XrX?represent a ring system of formulas ta), (e). (0, (k) or (r). Further described is a compound in which X\- X<. represent a ring system of formula (a) or (e). A compound is described in which XrXs represent a ring system of formula (a).

10067} In the following example run. XrXs represent the ring system of formula (j).

100681A compound is described in which when X,, X. and X* represent C and X-, represents nitrogen,

A represents phenyl. Bje is a group different from a heterocyclic group.

|0069|A compound is described in which when X|, X>. XLi X< represent C and X; represents nitrogen. A represents pyrimidinyl. B represents a group different from the heterocyclic group.

|0070|A compound is described in which when X,. X, X, and X< represent C. X> represents azole. A represents pyrimidinyl, B represents a group different from a heterocyclic group,

100711A compound is described in which when X|, X; and X< represent C and X> and X represent nitrogen. then R" is a group different from -O.

100721 A compound is described wherein when X... X-, X_, and X, represent C. X represents azole. A represents thiazolyl.

R" represents a group other than -CONR"*R\

|0073|A compound is described in which when X , and X; represent eggs X; represents nitrogen. A represents a group other than pyrazinyl.

|0074|A compound has been described in which when X>X? X , and X:, represent C. X represents nitrogen. B represents a »hole other than phenyl.

|l)075| A compound is described in which when X represents nitrogen. X represents a group other than nitrogen. |00761 The ring system encompassed by the definition of A is shown in formula AI wherein B may be optionally substituted with I, 2, or 3 R<1>as shown in formula (I). Examples of ring systems A2-AI5 and A12a are further described:

(00771 Group A 12 can be any lautomer of imidazole eg A 12a.

|0078| A compound is described in which the A group is different from pyrazolyl. A compound is described in which the A group is different from imidazolyl.

100791 In one exemplary embodiment. A represents group A 1.

|0080| A compound is described in which A represents a group selected from one of the formulas A I to AK) and AI2-A15. A compound is described wherein A is selected from A2. Al-I and Air. A compound wherein A is selected from A2 is disclosed.

100811 A compound is described in which A represents a 5- or 6-membered aromatic group.

|0082| A compound in which A represents a 5-membered aromatic group is described

|0083| A compound is described in which A represents a non-aromatic group.

100841 A compound in which A represents a 6-membered aromatic group is described

|0085| In one version. A represents phenyl.

10086|A compound is described in which A represents pyridin-3-yl.

|0087| A compound is described in which A represents a monocyclic aromatic carbocyclic or beterocyclic ring system having. for example. 5, 6 or 7-membered ring.

10088 ]A compound in which A represents a 6-membered carbocyclic ring is described.

|0089|A compound is described in which A represents a thenyl group (ie ring system of formula Al) optionally substituted with one or more (eg I. 2 or 3) R<1> groups. In one exemplary embodiment, A represents a phenyl group (ie, a ring system of formula A1) optionally substituted with I. 2 or 3 IV groups. In one example implementation. A represents unsubstituted phenyl or phenyl substituted with a -(Cl 10,-CONR'R' (e.g. -CONH..). <<ll \ (e.g. -CN).

|0090| A compound is described in which A represents a monocyclic aromatic carbocyclic or heterocyclic ring system having. for example. 5. 6 or 7-membered ring. A compound in which A represents a 6-membered carbocyclic ring is described. A compound is described in which A represents a phenyl group (i.e. a ring system of the formula Al > or a pyridyl group (i.e. a ring system of the formula A2 or A3) optionally substituted with one or more (e.g. I, 2 or 3) R* groups. In one exemplary embodiment, A represents a phenyl group (i.e. a ring system of the formula AI) optionally substituted with I. 2 or 3 R'<1> groups.

|0091|In one example implementation. A represents unsubstituted phenyl or phenyl substituted with -(CH.), -CONR'R-(eg -CONH;.). -(CH^-CN (eg -CN). halogen (eg fluorine). ( , " alkyl (eg methyl). C,.,, alkanol (eg - CH,OH) or -OR" (eg methoxy or -()('!!(Me! ) group.

100921 A compound is described wherein A represents a group other than pyridinyl or pyrazinyl when B represents phenyl, pyridyl or pyrazinyl.

|0093|A compound is described in which A represents a group other than pyr/mil. A compound is described in which A represents a group other than pyrimidinyl. A compound is described in which A represents a group other than pyridinyl or pyrimidinyl. In the following performance example. A represents unsubstituted phenyl.

|0094| A compound is described in which A is a 6-membered monocyclic aromatic carbocyclic or heterocyclic

ring system (eg pyridyl). substituted with NH-B-tR<1>), at position 3 or 5.

100951 In one exemplary embodiment. A represents phenyl substituted with NH-B-(R') at position 3 or 5. When A represents phenyl. in one exemplary embodiment of NII-B-fR1), is present at the 3-position of the phenyl relative to the attachment position to X,.

|0096| A compound is described in which A is a 6-membered monocyclic aromatic carbocyclic or heterocyclic

ring system (eg pyridyl). substituted with NH-B-(R'), at the 5-position and further optionally substituted with one R" group at the 3-position.

|0097|In one exemplary embodiment, A is phenyl substituted with NH-B-'R1),,

at the 5-position and further optionally substituted with one R" group at the 3-position

10098] Examples of aromatic ring systems covered by the definition of B-NH- are shown in the following formulas B2-B9 and BI3-B47. especially B2-B9 and B13-B45. Examples of ring systems described below are BI and B10-BI2.

Specific examples of B rings include B4 and B°. Further specific examples of B rings include B19-21, B22. B24. B25. B27-36. B38-40. B42 and B44.

|0099| A compound is described in which when V represents CH ., one example of an aromatic ring system encompassed by the definition of B-NH- is shown in the following formula B48:

101001 Examples of saturated or partially saturated ring systems included in the definition of B-NH- are shown in the following table 1:

(01011A compound is described in which B represents -V-aryl. A compound is described in which V represents a group different from -C(H)(Me)-. A compound is described in which V represents a bond. A compound is described in which the aryl »hole in B represents a phenyl group.

|0102|In one example implementation. B represents -VV-heterocyclyl.

[01031] A compound is described in which VV represents a group other than -C"(H)(Me)-. In a further embodiment, VV represents a bond.

|0I04|In one exemplary embodiment, when B represents a -W-heterocyclyl group. VV represents connection.

101051 A compound is described in which the aryl or heterocyclyl group B represents a monocyclic aromatic carbocyclic or heterocyclic ring system having, for example, 5.6. or 7 ring members (eg phenyl, pyridyl. pyrazinyl. triazolyl or thiadiazolyl).

[01061 In one embodiment, the heterocyclyl group B represents a monocyclic aromatic heterocyclic ring system having for example 5, 6, or 7 ring members of I upi. pyridyl. pyrazinyl. triazolyl or thiadiazolyl). In a further embodiment, the heterocyclyl group B represents a 5- or 6-membered heterocyclic ring (eg pyridyl. pyrazinyl. triazolyl or thiadiazolyl). In a further embodiment, the heterocyclyl group B represents a 5- or 6-membered heterocyclic ring (eg pyridyl. pyrazinyl. triazolyl. oxadiazolyl. imidazolyl or thiadiazolyl). In a further embodiment, the heterocyclyl group B represents a 5-membered heterocyclic ring selected from compounds of formula B'. B1' and IV;

wherein Xa is selected from NH, CH. and S: Xb is selected from C, N, O. and S: Xc is selected from N, and (): Xd is selected from C, N, O, and S: Xe is selected from C and N and is an NH attachment site; wherein the dotted line may represent a single or double bond: Xa is selected from NH. CH, and S: Xb is selected from C. N. O. and S: Xc is selected from C. S and N: Xd is selected from C, N. O. and S; Xe is selected from C and N and represents the NH binding site:

where the dotted line -' lim can represent a single or double bond;

Xa is selected from NH. CH, and S: Xb is selected from C. N, 0, and S: Xc is selected from C. N, O. and S: Xcl is selected from C. N.

O, and S: Xe is selected from C and N and - " represents the attachment site for NH:

101OTJ In further execution. heterocyclyl group B represents oxadiazolyl. imidazolyl, triazolyl or thiadiazolyl. In a further embodiment, the heterocyclyl group B is triazolyl or thiadiazolyl. In further execution. heterocyclyl group B represents Ija tiadiazo 1 and I.

[010S| In one performance. q represents 0 or I. When q represents I. in one embodiment. R<1> represents Cu, alkyl (eg methyl), Kadaq represents I, in an alternative embodiment. R<1>represents -(CH,<)„NR<S>R<>>(eg -NH?) In a further embodiment, q represents 0.

101091 A compound is described in which X- represents CH or nitrogen.

101101 A compound in which X represents CH is described. nitrogen or C~0.

|01111 Described is a compound in which R: represents a -COOR' group (eg -COOH). In the further derivation, R* represents the -CONR'R<*> group.

10112| A compound is described in which R represents the -() ()RX group.

(01 13| In one embodiment, Rx is C1, alkyl (e.g. methyl, ethyl or isopropyl) or C:.x cycloalkyl (e.g. cyclopropyl.

cyclobutyl or cyclopentyl).

|OI14|A compound is described in which when R<:>represents a -COR" group. R<:>represents Cu, alkyl (eg methyl, ethyl or isopropyl) or C1-6cycloalkyl (eg cyclopropyl, cyclobutyl or cyclopentyl).

|0115|A compound in which R" represents hydrogen is described.

10116|A compound is described in which R" represents alkoxy (e.g. unsubstituted (alkoxy). 10117| In one exemplary embodiment, and Ri R* represent hydrogen or C, " alkyl (e.g. methyl).

(0118| LJ in the following exemplary embodiment, one of R 1 R s is hydrogen and the other is alkyl (eg methyl, ethyl or isopropyl) optionally substituted with an -OR' group

(e.g. -(('ll :-O-V1e); C-,.Mcycloalkyl (e.g. cyclobulyl): or heterocyclyl (e.g. lyophenyl). In a further embodiment, one of R" and R's represents hydrogen. and the other represents C1-" alkyl (e.g. methyl).

|0II9|A compound is described in which R and R<s> together with the nitrogen atom to which they are attached form a heterocyclyl ring containing a nitrogen optionally substituted with one or more (eg 1, 2 or 3) R<1>' groups.

In the following embodiment, R and R<*> together with the nitrogen atom to which they are attached form a heterocyclyl ring containing a nitrogen optionally substituted with 1, 2 or 3 R 1' groups.

|012I|A compound is described in which R and R* together with the nitrogen atom to which they are attached form a heterocyclyl ring containing nitrogen optionally substituted with 1,2 or 3 R'<1> groups.

10122) In a further embodiment R<7> and R<s> together with the nitrogen atom to which they are attached form a heterocyclyl ring containing nitrogen optionally substituted with 1, 2 or 3 R' groups.

(01231 Described is a compound in which R<7> and R<s> together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl ring (e.g. azetidinyl or pyrrolidinyl) optionally substituted with one or more (e.g. 1.2 or 3} R1' groups (e.g. -ORx (e.g. -OM), halogen (e.g. fluorine). - Y ari I (e.g. -phenyl). In further embodiments, R and Rs together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl ring (eg, azetidinyl).

(01241In a further embodiment. R<7> and R<1*> together with the azole atom to which they are attached form a nitrogen-containing heterocyclyl ring (eg azetidinyl or pyrrolidinyl) optionally substituted with one or more (eg I, 2 or 3) R<1>' groups (eg -OR<x>(eg -OH). halogen (eg fluorine) or -Y-aryl (eg -phenyl). Upon further derivation, R and R* together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl ring (eg, azetidinyl).

101251 In one embodiment, Y represents a bond or -O-(CH0,- (eg, -O-CIC-).

(01261In one exemplary embodiment. Y and Z independently represent a bond. -CO-(CI ! •),-.

-COO-. - (CH,),,-. -NRMCH ■)„-. -(CH;)„-NR<X->. -CONR<s->, -NRX'<>, -S().NR<%-.>-NR<N>SOr.

-NR<x>CONR<>->. -NR<X>:SNR<>->, -O-(CH,)„ -(CH;),-O-, S-. -SO- or -(CM .),,-SC)i-.

|0127|In one performance. Y and Z independently represent -CO-. -O-(CH ),- or - NI 1 -(CI 1 (eg NH).

|0I28|In one performance. Y and Z independently represent -CO-. -0-(CH ),- or - NI 1-(CI 1 ■ i„-|0129| In one embodiment, Z represents a bond. CO. -i( I! >. (e.g. -CH -. -(CH,)- or -(CH,)-) or -()-. In a further

performance. Z represents -O-. -CO-. or -(CH;)"- (e.g. -Cll:). And in a further derivation. /. represents -(Cl-!i)"- (e.g. -

CH.,).

101301 In one version. Y and 7 independently represent a bond.

|01311 A compound is described in which R1' independently represents the R'<1> group or -V-alkyl or -/-heterocyclyl group, wherein said aryl and heterocyclyl groups can be optionally substituted with one or v i se (e.g. 1.2 or 3) RM group.101321l) in one embodiment. R<1>' independently represents the R'<1> group or -Y-aryl or -/.-heterocyclyl group, wherein said aryl and heterocyclyl groups may be optionally substituted with 1,2 or 3 R<:>| groups.

10133]A compound is described in which R\ R'. R<*>independently represent hydrogen or methyl. A compound is described in which R<c>, R<1>, R" represent hydrogen.

|0134|In one performance. Rc and R<1> independently represent hydrogen or methyl. In a further embodiment, R* and R<1> represent hydrogen.

|0135|In one embodiment, n represents I.

|0I36|The compound of formula (I'c) or (Td) is described:

whereby

A represents an aromatic carbocyclic or heterocyclic group which may be optionally substituted with one or more (eg 1, 2 or 3) R'1 groups: B represents an aromatic or non-aromatic carbocyclic or heterocyclic group: RJ and R' independently represent hydrogen. CY„ alkyl. C>.„ alkenyl. (,'..,. alkynyl. (',.,, cycloalkyl. C> s cycloalkenyl. (",.<.

alkanol, haloC,.,, alkyl.-(CI 1:)"-NR'R>. -(Cl I ,),X'OOR'". (Cl I .)„-()-(('! 10,,,-OH. -(CrU, -aryl. -(CH,)„ O-aryl. -

(C112}-heterocyclyl or (CH-1)M-O heterocyclyl

wherein said C,.,, alkyl. C1, alkenyl. ('.-.,, alkynyl, C 5-8 cycloalkyl, C:-x cycloalkenyl, aryl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) R'<1> groups;

R\ R- and R independently represent hydrogen. C, ,, alkyl. Calkenil. C..„ alkynyl. C|.,, alkanol. hydroxy. Cj.„

Alkoxy. haloC,.,-, alkyl. -CO-(CH?)„-(-,.„ alkoxy.C 1 s cycloalkyl or cycloalkenyl;

R' represents -CONRV. -COR<*>or COOR' group:

R<7> and R* independently represent hydrogen. C,.,, alkyl. O.,, alkenyl. C-1, alkynyl. C 1 -C cycloalkyl, C 1 -C 4 cycloalkenyl. aryl. heterocyclyl or R and R<s> together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclyl ring, wherein said (?,.„ alkyl. aryl and heterocyclyl may be optionally substituted with one or more (e.g. I. 2 or 3) R3 group: R<*>represents halogen. alkyl. C\„ alkenyl. C\,, alkynyl. C: s cycloalkyl. (.%.„ cycloalkenyl. -OR\ -0-(CH:.)„-OR\ haloC|.,, alkyl. haloC,.,, alkoxy, C,„ alkanol. O. -S. nitro. -CCH.K-CN. -S-R\ -SO-R\ -SO:-R\ - COR\ -<CRvRM,-COOR'', (( I |,),-( 'ONRxR>. -(CHT-NI~CR\ -(CHA-\RVOR'. (CH ) -NR'MK-K'. -(>0< >\RVR\ - C! I i -\IC< <) K . -(MCI! and (R'R'-K II i. OR or -•:('! I-SO NiR R groups: R<l>and R<1>' represent an R" group or -Y-aryl or -Z-heterocyclyl group, wherein said aryl and heterocyclyl groups can be optionally substituted with one or more (e.g. 1, 2 or 3) R" groups);

Y and Z independently represent a bond. -CO-<CH.)%-. -(XX)-. -((!!..)„-. -Nl<C-><CH;)n-. - (CH A.-NR'-. -CONR"-. - NRTO-. -SO,NR\ -NR<N>SO?-. -NR<x>CONR--. -NRVCSNR'-. -0-(CI I ■),-. -(CH.0.-O-. -S-. -SO- or -(CH,)5-SO?-;

m and n independently represent an integer from 1-4;

s and t independently represent an integer from 0-4:

q represents an integer from 0-2:

aryl represents a carbocyclic ring;

heterocyclyl represents a heterocyclic ring;

or a pharmaceutically acceptable salt thereof. solvate or derivative.

101371 In one embodiment, a compound of formula (Te) or (l'd). Y and Z independently represent a bond. -CO-(CI lj),-, - COO-. -(Cl l:), r. -NRV-(CI !,)„-. - (CH-ln-NR<1->. -CONRV -NR<v>CO-. -SO,NRv-, -NR<x>SOr. -NRTONRV - NRvCSNRy-, -0-(CH:)s-. -(CH,h-0-. -S-. -SO- or -(ClI .K-SO-:|0I38|In one embodiment, the compound of formula (1) is the compound selected from examples 1-4, and in a further embodiment, the compound of formula (I) is the only one from example 2.

|0139| In the specification, references to formula (I) include formulas such as (I"). (Ta). (I'b). and subgroups. Examples or exemplary embodiments of formulas (I), (I<*>) (Ta), (l'b). (I'c) and (l'd). unless the context indicates otherwise.

|0I40|That's right. for example. calling engineer altana for therapeutic applications. pharmaceutical formulations and processes for obtaining compounds. which refer to formula (I), should be understood as references to formula (1). (D. (Well).

(l'b). (Te) and (l'd). and subgroups. examples or examples of derivations of formulas (1).([').(I"a). (l'b). (I'c) and (l'd).

|01-411 Similar fractures. where preferred embodiments, exemplary embodiments and examples for compounds of formula (1) are given. they can also be applied to formulas (I). (I"), (l'a). (l'b). (I'c) and (l'd). and subgroups, examples or derivations of formulas (I). (I'), (l'a). (l'b). (I'c) and (l'd). unless the context indicates otherwise.

Methods for obtaining compounds of formula (I)

|0142|In this section, as in all other sections of this application, unless the context indicates otherwise, the recitation of formula (I) also includes all other subgroups and examples thereof defined herein.

|()143|Compounds of formula (I) can be obtained by methods of synthesis well known to a person skilled in the relevant field. Compounds of formula (I) are particularly readily obtained by palladium-mediated coupling herniation between aromatic chloros. bromo, iodo, or pseudo-halogen. such as trifluoromethanesulfonate (triflate) or (oz.ylate compounds, and aromatic boronic acid derivatives or stannanes. For the synthesis of these compounds, the Suzuki coupling hernia is particularly generally applicable. The Suzuki reaction can be carried out under the usual conditions. in the presence of a palladium catalyst, such as his(tn-i-buiylphos!ln)pa]adiiim. ieirakis-(iriphenylphoslin)palladium or pallacyclic catalyst (e.g., described in Bedfnrd. C.S.J., 1540-1541) and bases (e.g., potassium carbonate), which will be discussed in more detail below. For example, a solvent system

aqueous ethanol. or ctar. such as dimethoxyethane or dioxane. and the reaction mixture is usually subjected to fermentation. for example, up to a temperature of 80 X or more, e.g. temperatures above 100 C.

|0144|In the process sections, references to R and R" are used to indicate the groups defined in R and R\ or their protected forms.

|0145|As shown in Scheme IA, the imidazo 1.2-a|<pyridine ring can be synthesized from commercially available starting materials as indicated below to give the 3.7-disubstituted ring.

|0146|2-Amino-isonicotinic acid methyl ester in a suitable solvent and base can be cyclized under reflux with chloroacealaldehyde to give the imidazopyridine ring,

101471 For the synthesis of the R'1 group of compounds of formula (I), the carboxyl ester is hydrolyzed. for example. using standard ester hydrolysis conditions such as aqueous base and heating. The carboxylic acid or its activated derivative can then react with the corresponding amine to form the amide (Scheme I A ).

|0!48|The coupling reaction between a carboxylic acid and an amine is primarily carried out in the presence of a reagent of the type commonly used in the formation of peptide bonds. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al. 1. Amer. Chem. Soc. 1955. 77, 1067), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (designated herein as I,!)( or I i>,\( , but also known in the relevant art as EDC1 and VVSCDI) (Sheehan et al. al.. 1. 1961. 2525). telrafluoroborate ■ ' B11 and and phosphonium-based coupling agents. such as 1-benzo-triazolyloxytris-(pyrrolidito)phosphonium hexafluorophoslate (PvBOP) (Castro et al. Tetrahedron Letters, 1990. 31, 205). Carboxyimide-based coupling agents are primarily used in combination with 1-hydroxy-7-azabenzotriazole (I IOAt) (L. A. Carpiuo..1. Amer. Chem. Soc. 1993. 115. 4397) and 1-hydroxybenzotriazole (HOBt) (Konig et al. Chem. Ber.. 103. 708. 2024-2034). Preferred coupling reagents include TBTU. EDC (EDAC) or DCC in combination with IOAt or HOBI.

|0149|The coupling reaction is usually carried out in non-aqueous. nonionic solvent such as acetonitrile. 1,4-dioxane, dimethylsulfoxide, dichloromethane. dimethylformamide or N-methylpyrrolidine. or in an aqueous solvent. optionally together with one or more miscible co-solvents. The reaction can be carried out at room temperature or. when the reactants are less active (for example, in the case of electron-poor anilines bearing electron-withdrawing groups such as sulfonamide groups) at a suitable elevated temperature. The reaction can be carried out in the presence of a base that is not involved in the reaction, for example. tertiary amine. such as triethylamine or ,V,.V-diisopropylethylamine,

(01501 As an alternative, a reactive carboxylic acid derivative can be used, eg anhydride or acid chloride.

Reaction with a reactive derivative such as an anhydride is usually carried out by mixing the amine and anhydride at room temperature in the presence of a base. such as pyridine.

101511 Amines for use in the reaction may be obtained from commercial sources or may be obtained by any of a number of standard synthetic methods well known to those skilled in the art, for example, see

AihuiKdl OrRiuih- C ' hvinistrv by Jerrv Marcli. A. edition. John VV'i les <Ji Sons. 1992. and Organic Sweetfil' Si' s. volumes

1-8. John William. edited by Jcremiah P. I-Teeman (ISBN: 0—171 -31192-8). 1995 and \ also the methods described in the experimental section below. For example. the corresponding nitro compound can be reduced to give the corresponding amino compound. Reduction can be carried out using standard methods, such as catalytic hydrogenation. for example. in the presence of palladium on carbon in a polar solvent such as ethanol or dimethylformamide. at room temperature. As an alternative to that. reduction can be carried out using a reducing agent, such as stannous chloride in ethanol. usually with heating. for example. to the reflux temperature of the solvent.

|0152| Imidazole 1,2-a)pyridine-7-derivative. for example. methyl ester or amide imide/.o| 1,2-α|pyridine-7-carboxylic acid, in a suitable solvent can then be iodinated. for example. using N-iodosuccinimide at room temperature.101531 Appropriate functionality can then be added at the halogenated positions, e.g. using metal-catalyzed reactions. Suitable functionalized boronic acids, trifluoroioboronates or their boronate esters can in particular react with aryl halides. This transformation, which is generally known as the Suzuki reaction, is discussed by Rossi et al (2004). Svnihesis 15.2 1<1>«.

101541 The Suzuki reaction is often performed in mixtures of water and organic solvents. Examples of suitable organic solvents include toluene. tetrahydrofuran. 1.4-Dioxane. 1.2-Dimethoxyethane. acetonitrile. N-methyl pyrrolidinone, ethanol, methanol and dimethylformamide. The reaction mixture is usually subjected to heating. for example. up to a temperature of more than 100 °C. The reaction is carried out in the presence of a base. Examples of suitable bases include sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate. Examples of suitable catalysts include bis(tri-t biethylphosphin)<p>aladium(0).tris(dibenzyldenacetone)dipalladiini(0).bis(tritethylphosphin)n)palladium(II) chloride, palladium(II) acetate. etrachis(triphenylphosthln)palladium(0). bis(tricyclohexylphostine) palladium(O). (I.r-bis(dipheuylphostuio)-ferrocene |dichloropalladium(II). dichlombis(tri-o-[olylphosphln)palladium(II). 2"-(dimethyl lanino )-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex and 2-(dimethylamino)ferrocen-1-yl-palladium(II) chloride dinorbornylphosphine complex. In some cases, they may be added additional ligands to facilitate the coupling reaction. Examples of suitable ligands include tri-t-butylphosphine. t.3-bis{diphenyl!bisphino)propane. 2-(di-t-butylphostino)biphenyl. 2-dicyclohexyphosphino-2<*->(n,n-dimethylamino)-bilenyl. tri-o-tolylfostln. 2-(dicyclohexylphoslino)bi phenyl. 2-dicyclohexylphostino-2'.4<*>.6'-triisopropylbiphenyl. tri(2-furyl)phosl'ine, 2-dicyclohexylphenyl-2',6'-dimethoxybi-phenyl and 2-di-tert-butyphostilno-2',4',6'-triisopropylbiphenyl.

|0I55|Other examples of possible functionalization of metal-catalyzed halides are reactions with organotin reagents (Steele's reaction), Grignard reagents, and reactions with nitrogen miclcotllin. A general overview and other leading references for these transformations are presented in Talladium Reagents and Catalvsls' (.liro Tsuji. Wiley. ISBN 0-470-85032-9] and Mandbook of OrganoPalladium Chemistrv l'or Organic Svmhesis (toni I. edited by Eiichi Negishi. VVilev. ISBN 0-471-31506-0).

|0156|In particular, one of the reactions that can be performed is the Buchwald-I Hartwig-type reaction (see A'er/i'ir.J, I-'. Hartwig (1998). Angewv. Chem. Int.l-. d.37. 2046-2067) which provides a catalyzed synthesis of aryl amines

palladium. The starting materials are aryl halides or pseudohalides (for example, triflates). and primary or secondary amines, in the presence of a strong base. such as sodium /e/r-butoxide. and a palladium catalyst, such as tris-<dibenzylideneacetone)-dipalladium (Pd?(dba)i>. or 2,2'-bis(diphenylphostino)-1' I -binal'tyl (BINAP).

10157JEspecially for the purpose of synthesizing compounds of formula (I) aryl lyalide can be reacted with 3-aminobenzeneboronic acid using a suitable metal catalyst, e.g. bis( tri phen iltbsfln )<p>aladijunt( 1<1>) chloride, to form the amino precursor for the formation of the secondary amino bond.

|0I58| This sequence of reactions discussed in Scheme A may be interchanged with that discussed in Schemes IB or IC.

|0I59|In Scheme IB. The methyl ester of imidazo 1,2-pyridyl-7-carboxylic acid is first iodinated. so a metal-catalyzed coupling reaction is performed, before the conversion of the methyl ester to the amide group R\ |0160|In Scheme IC. imidazo) 1.2-a]pyridin-7-amide is synthesized directly from 4-amide-pyridin-2-ylainin, and then iodinated and used in a metal-catalyzed coupling reaction. This reaction scheme is particularly suitable for the synthesis of compounds where R" is CONH,.|0I6I|Alternatively, 4-chloro-pyridin-2-ylamine or 44-ironio-pyridin-2-ylamine in an appropriate solvent and base can be cyclized under reflux with lyloroacetaldehyde to give a 7-halo-imidazopyridine ring (as shown in Scheme 2). The halogen functionality at the 7-position is an imidazo The 1,2-a]pyridine can then be converted to the amide by one of the two routes shown in Scheme 2. The 10162'halide can be converted to the nitrile using CuCN in N-methylpyrrolidine under reflux (for example, as described in Funhoff. D..I.II el al. Angewv. Chem. Int. P.dj. 1986. 25(8). 724) or CuCN in DMF, which is then hydrolyzed with an alkali metal hydroxide, such as potassium hydroxide. that acid and or amytl were obtained. Once a mixture of acid and amide is formed, they can then be separated by standard methods, such as chromatography. The acid can then be coupled with an amine of formula under typical amide coupling conditions of the type described above to give a compound of formula (I).|0I63|Alternatively. the halide can be converted to the acid using n-butyllithium or magnesium and subsequent reaction of the intermediate with the agent for carbon and lac and ju. such as C(K) to give the carboxylic acid for use as a compound of formula (I) or for conversion to an amide or ester. The amide can be obtained directly from the halide, or by transmetallation with "BuLi followed by quenching with the appropriate isocyanate (Pansegran. P.D. et al. JACS. 1988, 1 10. 7178). or by carbonylation with carbon monoxide and in the presence of a suitable amine and catalytic tP.P'-l.3-bis(di-i-propylphosph<i>no)pro<p>anl[P-l.3-bis(di-iso<p>ro<p>yl-phosRno)pro<p>ati|palladiurne(0) in a solvent such as xylene. with heating (eg, up to 150 CC) (eg, as described in Ben-David. Y. et al. JACS. 1989, 111(23). 8742). acid, and then undergo conversion to an amide using the standard coupling conditions previously described or be esterified to an ester. The halide can also be converted directly to the ester with use of carbon monoxide, a palladium catalyst and the appropriate alcohol. Then this compound of formula (I) can be hydrolyzed to an acid, or it can be hydrolyzed to an acid and converted to an amide. or it can be converted directly to the amide. The bilaccode halide can be converted directly to the dimethylamide using trimethylsilyldimethyl amide and reaction with bistri-butylphosphopalladium and heating to 100 C as described in Cunico. R.F., Organ and Letters. 2002. 4 (24). 4357.{0I66|Other conversions of aromatic bromides to aromatic aldehydes can be performed using Steele's carbonyl synthesis (Steele. JACS. 1983. 105. 7175). or the Bodroiix-Chichibabin synthesis of aldehydes described in Einchom. J. Tetrahedron I. et.. 1983. 27. 1791. The aldehyde can then be acid oxidized and converted to an amide as described above.|0J67|Polyfunctional 2-amino-5-broniopyridines or aromatic bromides can be converted to an aldehyde by a Grignard-type formation and quenching with DMF (Vlisra. Bioorg. Med. Chem. I.ett., 2004. 14(11). 2973) or they can be converted to the ethyl ester by standard palladium carbonylation in the presence of an alcohol (Cheung, M. Heterocvcles. 2001. 55. 1583).[0I68|Alternatively. 4-methyl-pyridin-2-ylamine can be used in the cyclization reaction to give the 7-methyl-imidazo[1,2-a]pyridyl ring, which is alternatively commercially available. The methyl can then be oxidized to an aldehyde using Fluoride reactions or carboxylic acid using an oxidizing agent such as permanganate. The Ftard reaction involves the direct oxidation of an aromatically or heterocyclically bound methyl group to an aldehyde using chromium I chloride.|0169|Alternatively. ethyl imidazo[1.2-a]pyridine-7-carboxylate. which is also commercially available, can be used as a starting material for amide conversion or iodination and metal-catalyzed reactions.|0I70|Ketones. where R is COR\ can be synthesized from the corresponding carboxylic acid via N.O-dimethylhydroxamic acid (Weinreb amide) or N-mcyyl.O-t-butyl hydroxamic acid (Weinreb type amide) as an intermediate and subsequent reaction with the corresponding Grignard reaction (l.aheeuvv, O. et al Tetrahedron I.ett 2004. 45 (38), 7107-71 10.). Derivatization with the appropriate Weinreb amide using N.O-dimethylhydroxylamine hydrochloride as described in I... De l.uca. Mr. Giacomelli. M. Taddei, .1. Org. Chem.. 2001. 66, 2534-2537. Conversion of the standard aromatic Weinrech<g>amide to a methyl ketone requires melylene-trtpheni 1 - Iainbda*5*-fbsphane in a solvent such as tetrahydrofunin. as stated in Murpliv. JA et al Org Lett 2005. 7(7). 1427-1429.[01711 Alternatively. ketones can be prepared from chlorides using vinylethertin (Steele's type) coupled to a haloaromatic or haloheteroaromatic. For example. acetyl ketone can be obtained by heating tributyl-(1-ethoxy-vinyl)-stannane. lithium chloride and (triphenylphosphine)-palladium(0) ethers in a solvent such as acetonitrile or by a Fleck-type reaction, as reported in Mo. J. Angewv Chem. Ini Kd. 2006. 45(25). 4152. |0I72|The compounds of formula (I) can be obtained using 3-aminobenzenechoronic acid in the Suzuki reaction and subsequent derivatization. In particular, as shown in Scheme 3, the introduced amino functionality can be used for the synthesis of secondary amino compounds 101731 Primary amines can be obtained by reduction of the corresponding nitro compound under standard conditions. Reduction can be done, for example. by catalytic hydrogenation in the presence of a catalyst, such as palladium on carbon, in a polar solvent, such as ethanol or dimethylformamide. at room temperature.|0174|Compounds of formula (I) containing a secondary amino group, can be obtained from. amino compounds by numerous methods. Reductive animation with an appropriately substituted aldehyde or ketone can be carried out in the presence of a number of reducing agents (see Advanced Organic Chemistry by Jerrv March, 4"' Edition. John Wiley & Sons, 1992. p898-900). For example, reductive animation can be carried out in the presence of sodium triacetoxyborohydride in the presence of an aprotic solvent, such as dichloromethane, at or near ambient temperatures. They can also be obtained by reacting the amino compound in a nucleophilic displacement reaction, when the reagent contains a leaving group such as halogen. jthiadiazol-2-ylamino)-phenyl boronic acid pinacol ester in the Suzuki reaction with the appropriate substituted imidazo(1,2-a]pyriniidine. These can be synthesized as described herein.|0176|Alternatively the secondary amine can be formed by cyclization of the appropriate group to form a ring. Aminothiadiazole compounds can be synthesized as described in Scheme 4.

|0177|This involves the reaction of an amino compound in an anhydrous solvent e.g. toluene. with I. 1'-thiocarbonyl-2(1H)-pyridonoin. Typical reaction conditions are heating for 1 hour. gradually and then treated with hydrazine hydrate to give thiosemicarbazide. It is then cycled under conditions. as via the addition of diethyl chlorophosphate in drops. This may also generate a substituted cytization product and therefore separation may be required.

|0178|Substituted amino-heterocyclic groups may be formed by known ring-forming reactions. For example amino-triazole (eg 3H-[1,2,3]triazol-4-yl)-amine can be formed by reacting sodium nitrile in H.O with an amine in acid eg. 2N HCl, followed by the addition of aminoacetonitrile hydrogen sulfate in l-UO. After an appropriate period of time NaOAc is added and rearrangement to the desired heterocycle is achieved by heating in a solvent e.g. ethanol, during 16 hours.

|0I79|Suitable starting material and reagents for these reactions can be obtained commercially or by any of a number of standard synthetic methods well known to those skilled in the art, viz. for example. Advanced Organ and Chemistrv. by Jerry March. 4th edition. John William & Sons. 1992 and Organic Syntheses. volumes 1-8. John William. edited by .leremiah P. Freeman (ISBN: 0-47 1-31192-8). 1995 and see also the methods described in the experimental section below. For example. a number of suitable functionalized aniline and amino pyridine starting materials, and metal catalysts are commercially available.

|0I80|Many borates, for example, boronic acids, esters or irilluoroborates. which are suitable for obtaining compounds according to the invention can be obtained commercially, for example. from the company Boron Molecular l.imited from Noble Park. Australia, or from Combi-Blocks Inc. from San Diego. USA. If the corresponding substituted wrinkle! cannot be obtained commercially, then it can be obtained by methods known in the relevant field, for example, as described in the review article by Miwaur. N. and Suzuki. A. (19951Chem. Rev. 95. 2457. Accordingly. borates can be obtained by reacting the appropriate bromo-compound with an alkyl lithium. such as butyl lilium. and then reacting with a borate ester e.g. ('PrOhB. The reaction is usually carried out in a dry polar solvent. such as tetrahydrofuran at a reduced temperature (e.g. -78 C). Boron and esters (e.g. can also be obtained from a bromo-ester such as /.Y(pinacolalo) phosphine. such as //7.dibenziiidenaceion. is carried out in a polar aprotic solvent DMSC) with heating to a temperature of approx 100 C. for example. about 80 "C. The resulting borate ester derivative can, if desired, be hydrolyzed to give the corresponding boronic acid or can be converted to the trifluoroborate,

|(I18I|All the reactions described above can be used for the functionalization of alternative heterocyclic structures of formula (I), whose synthesis is shown below.

101821 When they are synthesized. then a series of functional group conversions can be applied to the substituted imidazopyridine compounds to give other compounds of formula (I). For example. some of the following reactions can be used for hydrogenation. hydrolysis, deprotection and oxidation to convert one compound of formula (I) into an alternative compound of formula (I).

Pyrazolol LS-aJpyritri idiniXrelerentnj .example)

The 101S31pyrazolo1,5-a]pyrimidine matrix can be synthesized from the appropriate suppressed aminoptrazole (VI) and fragments (VII) as shown in Scheme 5A. where R:, can be hydrogen or A-NH-B-fR'),,. This can be carried out by a one-step or two-step process, where X;1 and X1 are electrophilic carbons (ie, carbonyls, masked carbonyls, ie, acetals, enamines, conjugated alkenes or alkynes) (Perkin 1. J.C.S. (1979). 3085-3094). Xtje is a suitable substituent of group R; or groups such as halogens or pseudo halogens or methyl which allow R» to be introduced by reaction as described herein. Cyclization of pyrazole (VI) with an appropriately substituted free or masked 1,3-dicarbonyl derivative can be applied to obtain pyrazole-substituted 1,5-pyrimidines. The cyclization usually takes place in an alcoholic solvent or in toluene or in acetic acid, and may have additives present. such as piperidine. nalrium ethoxide, HCI. AcOH. p I sOII. or ZnCK (J. Med. Chem. (2001). 44 (3). 350-361: Buli. Korean Chem. Soc. (2002). 23 ( I ). 610-612: Australian Journal of Chemistrv (1985). 38(1). 221-30).

|0184|Specific scheme of synthesis in order to obtain disubstituted pyraz.olo| 1.5-a|pyrimidine is shown in Scheme 513. The pyrazolopyrimidine ring is formed by reaction of substituted malonaldehyde as fragment VII with aminopyrazole. Substituted malonaldehyde can be substituted with methylol with latent functionality, e.g. halogen, as in 2-bromo-malonaldehyde. which allows for further derivatization at this position as in the scheme shown below using the reactions discussed here.

|0185|In the cyclization reaction. malonaldehyde in the solvent is added to 3-aminopyrazole. which is followed by acid e.g. glacial acetic acid. The reagents are then cyclized after heating under reflux, The compound of formula (I) can then be synthesized using the oxidation and coupling process discussed herein.

|0186|Compounds of formula (VI) and (VII) are known compounds or can be obtained analogously, by known methods. Many pyrazoles of formula (VI) are commercially available. Alternatively, they can be obtained by known methods, e.g. from ketones in the process described in EP308020 (Merck), or by the methods discussed by Schmidt in Helv. Chim. Acta. (1956), 39. 986-991 and Helv. Chim. Acta. (1958). 41. 1052-1060 or by conversion of pyrazoles of formula (VI) or compounds of formula (I), where R'' is hydrogen, nitro, ester or amide, in the desired R<1>functionality

by methods known to a person skilled in the relevant field. For example. when R 1 is halogen. then coupling reactions could be performed with tin or palladium herniation as described here.

(01871 Alternatively. pyrazolo 1,5-a]pyrimidine-6-carboxylic acid or aldehyde are commercially available and

can be used in the reactions described here for the synthesis of di-stituted pyrazolo| 1,5-aypyrimidine.

Pyrazolo[1,5-ylpyrazines (reference example)

[0I88|

|0189|Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodide under inert conditions in a suitable solvent and base. such as e.g. DMF'EUN. with elinyl-trimethyl-silane using a palladium catalyst, e.g. Pd(PPIh).ina at room temperature gives 2-bromo-5-trimethylisolanylethynylpyrazine. This material can be used without further purification and is reacted to form 6-bromo-2-trimethylsilanyl-pyrazolo 1,5-ylpyrazine using O-(mesitylenesulfonyl)hydroxylamine to form the N-amino adduct. This can then be cyclized by reaction with a base, e.g. K?CO* to form the pyrazolopyrazine core (Scheme 6).

101901 Appropriate groups can then be introduced by lyalo<g>enation and reaction of the latent functionality in metal-catalyzed reactions and amide conversions at other positions, as described herein.

Pirazok>[ and J-aJpiridiiii (reference example)

|OI91|O-(rnesitylenesulfonyl)hydroxylamine reacts with 3-suppository-pyridine under inert conditions to form N-aminopyridine which can be used without further purification (Sherna 7). Cylation of the N-adduct using the base (K,-CO.i) and 2-benz.enesulfonyl-.i-dimethylamino-acrylic acid methyl ester in an inert atmosphere affords pyrazolo[l..s-a]pyridine ester of 3-carboxylic acid. The carboxylic ester can be removed, for example, by saponification using sodium hydroxide to form the acid, and then by decarboxylation in polyphosphoric acid. The bromide can be then convert to the desired R group using the methods described here.

|0I92|Iodination with N-iodosuccinimide and the metal-catalyzed reaction of aryl halides can be used to introduce the desired functionality as discussed here. lmid azo|4,5-b]pyridines (reference example;|0I93|lmidazo(4,5-bJpyridine ring system can be constructed by reacting aniline with 2-chloro-3-amino pyridine, as described in J. Ileterocvclic Chemistrv (1983). 20(5). 1339 (Scheme 8). |0194|It is believed that the resulting bicyclic ring in Scheme 8 can be functionalized by halogenation or alkylation and converted to R' as described herein. A more functionalized intermediate could be obtained, for example, as shown in Scheme 9A, based on the methods described in US 06723735. the desired compounds of formula (I) were generated.

|0197|Alternatively. they can be synthesized as shown above in Scheme 9B.

Imidazo[4.5-c]pyridines (reference example)

|0198|3-Aryl-3H-imidazo[4.5-c]pyridine ring system can be constructed by reacting 3H-imidazo[4,3-c]pyridine with an aryl iodide, as discussed in Bioorg. Med. Chem. I. ett. (2004). 14. 5263 (Scheme 10).

|0199|It has been described that the regioisomeric products can be separated by chromatography. A possible way to further elaborate this material to obtain the desired substitution scheme is shown below (Scheme 11). |0200|Reaction with an oxidizing agent, such as 3-chloro perbenzoic acid, could be used to give the N-oxide which can be rearranged into a disubstituted 3H-imidazo|4.5-c|pyridine with several reagents e.g. POCh, SOCli. The regioisomeric products could then be separated by chromatography. By removing the halogen with potassium cyanide in DMSO or by reacting with platinum and Zn(CN). (Bioorg. Med. Chem. Lett.. 2003, 13 (9). 1591). a nitrile is obtained. which can be converted to the acid as shown above.10201) An alternative strategy is shown in Scheme 12. The synthesis of 6-chloro-31-imidazo|4,5-c pyridine is described in J. Heterocvclic Chem (1965), 2(2). 196-201. The chloro group can be changed as shown there. Subsequent elaboration to the N-aryl compound could then be carried out under the conditions shown in Scheme 10. 102021 1,5-Diaryl-1,1-benzoimidazole (reference prhn-r) 102031 The synthesis of 1,5-diaryl-1H-benzoimidazole is described in Bioorg. Med. Chem. I.ett (2003). 13. 2485-2488 (Scheme 13).

10204)Displacement of the fluorine from 4-bromo-1-fluoro-2-nitro-benzene with the corresponding aniline paid for by reduction and cyclization with triethyl orthoformate gives the bromo-benzoimidazole with the desired substitution scheme. The product can be further elaborated by bromide reaction as described herein to provide 1,5-disubstituted benzoimidazoles.|0205|1,5-Disubstituted benzoimidazoles can be synthesized using an analogous procedure to that described in Scheme 1 I.

Imidazof 1,2-cJpyrimidines (reference example)

|0206|Di-substituted imidazo 1,2-cypyrimidines can be prepared as shown in Scheme 14

|02071 This starts from 7-chloro-imidazo[1.2-c|pii-inidine. the synthesis of which is described in Yanai et al, Heterocyclic compounds. XVIII. Synthesis of imidazo)1,2-c|-pyrimidine derivatives. Yakugaku Zasshi (1974). 94(12). 1503-14. This material can then be further elaborated using any of the reactions described above. [0208|When the 3-position is an aryl or heteroaryl group, then the S\Ar group can be replaced by a standard palladium cross-coupling reaction using a similar technique as described here (Scheme 16).

102091 Alternatively. 6-chloropyrimid-4-ylamine can react to form a bicyclic ring system, and then convert chloro ti R? group.

102101Alternatively, 6-amino-pyrimidine-4-carboxylic acid can be used as starting material.

Iir.idazoll.?.-cjpiriinidiii-.š-oii (reference example)

|0211|3.7 disubstituted imidazoyl .2-c]pyrimidin-5-ones can be obtained from 7-chloro-6H-imidazo[l.2-e|pyrimidin-5-one (CAS number 56817-09-5). the synthesis of which is described in Maggiali et al (1982). Acta Naiuralia de l'Ateneo Parmense. 18(3), 93-101 and Bartholomew et al (1975) Journal of Organic Chemistry. 40(25). 3708-13.

1021217-Chloro-6l1-imidazo[1,2-cypyrimidin-5-one can be derivatized using nucleophilic substitution reactions such as Sto is S1Ar. to add functionality at position 7 (Scheme 17). The S..Ar reaction can be performed using potassium cyanide and then converting to the amide. This compound can then be iodinated as described above before further functionalization using the Suzuki reaction.

|0213|Alternatively. 7-Chloro-6H-imidazo|1,2-cypyrimidin-5-one could be directly iodinated to the lower intermediate for use in the reactions described here (Scheme 18).

|02I4|In addition. other oxo-heterocycles could be synthesized by hydrolysis from the corresponding chloro derivative. The protected compound would undergo hydrolysis with a base to give the pyridone. This could be done with NaOH (or

NaOH/H;0;) in fUO'MeOH or H:0/dioxane following the procedure described in the literature for the hydrolysis of chloropyridine (eg, Australian J. Chem. (1984). 37( 12). 2469-2477).

Imidazolyl,2-bPyridazine (reference example)

|0215|

The synthesis of the imidazo 1,2-b|pyridazine core can be carried out as described in Scheme 19 using the pyridazin-3-ylamine derivative.

|02I6| Many with methyl, carboxylic acids, carboxylic esters. or halidinia supsiiiuisaiia bicycline or

monocyclic aromatic compounds are commercially available. Because of the logo. these and other heterocycles can be synthesized directly from methyl, carboxylic acids, carboxylic esters, or halide-substituted bicyclic compounds or from methyl, carboxylic acids, carboxylic esters. or halidinium substituted monocyclic aromatic compounds using the cyclization reactions described herein.

|0217|Other heterocycles can be synthesized using well-known reactions, for example, as described in Comprehensive Heterocyclic Chemistrv I (edited by Katritzkv. A.R. and Rees. C.W. (1982) flsevier) and Comprehensive lleterocvclic Chemistrv II (edited by Katritzkv, A.R.. Rees. C.VV. and llf.V. Scriven. I .I V. (1996) Klsevier. ISBN 0-08-042072-9).

|0218|In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at an undesirable location on the molecule. Examples of protective groups and methods for protection and deprotection of functional groups can be found in Protective Ciroups in Organic Synthesis (Green. I. and VVuts. P.

(1999): 3rd edition: John Wiley and Sons).

|0219|The hydroxy group can be protected, for example, as an ether (-OR) or an ester (-OC(=O)R). for example. as: t-butyl ether: benzyl, benzhydryl (diphenylmethyl). or trityl (triphenylmethyl) ether: trimethylsilyl or t-butyldimethylsilyl ether: or acetyl ester (-OC(=0)CH1. -OAc). An aldehyde or ketone group can be protected, for example. as acetal (R-Cl l(OR),) or ketal (R>C(OR)»). respectively, in which the carbonyl group ( <'-•(')) is converted to Jietar ( T(OR):). reaction, for example. with primary alcohol. The aldehyde or ketone group is easily regenerated by hydrolysis using a large excess of water in the presence of acid. The amino group can be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: methyl amide (-NHCO-CIl;): ben/yloxy amide (-NHCO-OCII.C„IU. • Nll-Cbz): as t-butoxy amide

(-NIIC0-OC(CH,)u -NH-Boc): 2-biphenyl-2-propoxy amide (-NHCO-()C(fH,),C"„I-I, C, M<. -NH-Bpoc). as 9-fluorenylmethoxy amide (-NH-Fmoc), as 6-nitroveratrilox amide (-NH-Nvoc). as 2-trimethylsilylyloxy amide (-NII-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Alloc) or as 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec) Other protecting groups for amines, such as cyclic amines and heterocyclic N-1-1 groups, include tokenesulfonyl (tnesyl) groups and benzyl groups such as para-methoxybenzyl. (PMB) group. The carboxylic acid group may be protected as an ester. for example. as: C1-alkyl ester (eg methyl ester; t-butyl ester); C 1 -haloalkyl ester (eg C 1 -trihaloalkyl ester); triC,.- alkylsilyl-<C>,.-alkyl ester: or (..'<„ aryl-C,.- alkyl ester (e.g. benzyl ester; nitrobenzyl ester); or as amide. e.g. as methyl amide. The Hol group may be protected, e.g. as thioether (-SR), e.g. as: benzyl thioether: acetamidomethyl ether

(-S-CII.;MIC( (»Cl I;!.

|0220| Key intermediates in obtaining compounds of formula (I) are compounds of formula (II) and (111). New chemical intermediates of formulas (II) and (III) represent the next aspect.

102211 A further aspect is a process for preparing the compounds of formula (I) described herein. whose process includes:

(i) reaction of compounds of formula (II):

or a protected form thereof, with an appropriately substituted aldehyde or ketone: or (ii) reaction of a compound of formula (II):

or its protected form, with hydrazine hydrazide and then cyclization; or

(iii) reaction of compounds of formula (III):

or a protected form thereof, wherein Y is a group that can be converted to an amide. such as e.g. methyl, carboxylic acid, carboxylic ester. Halide:

and then conversion to amide:

and then removing any protecting groups present:

at the company are X,.i. A, B. R' and R' as seen here defintsatio; and optionally thereafter converting one compound of formula (1) into another compound of formula (1).

102221 According to the following aspect, a new intermediate product was realized, which is defined here.

Pharmaceutically acceptable salts, solvates or derivatives thereof

|0223| In this section, as in all other sections of this application, unless the context dictates otherwise, the recitation of formula (1) also includes all other subgroups and examples thereof as defined herein.

|0224| Unless otherwise specified. listing of an individual compound also includes its ionic forms, salts. solve. isomers. tautomers. N-oxides. e-.tre. prodrug. isotopes and protected forms, for example. as discussed below: and primarily its ionic forms, or salts or tautomers or isomers or N-oxides or solvates; and even more preferably its ionic forms or salts or tautomers or solvates or protected forms. Many compounds of formula (I) may exist in salt form. for example, acid addition salts or. in certain cases salts of organic and inorganic bases, such as carboxylates. sulfonate and rbsfatnc salts. All such salts are within the scope of this invention, and reference to compounds of formula (I) includes salt forms of the compound itself.

|0225| The salts of the present invention can be synthesized from a parent compound containing a base or acid radical by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties. Seleetion. and LJse. P. Heinrich Stahl (editor). Camille O. Wermuth (Editor). ISBN: 3-90639-026-8. hard cover. 388 pages, August 2002. In general, such salts can be obtained by reacting these compounds in the form of free acids or bases with the appropriate base or acid in a lead or organic solvent. or in a mixture of two, generally non-aqueous media. like Sto are ether. ethyl acetal. ethanol. isopropunol. or acetonitrile.

10226| Acid addition salts can be formed with a number of different acids, including inorganic ones. and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of the following: acetic. 2,2-dichloroacetic acid. Adipine. Alginic. ascorbic (eg L-ascorbic), l.-aspartic, benzenesulfonic. of benzos. 4-acetamidobenzoic acid. buterna. ( -) camphor. camphor sultonic. ( + )-(l,S")-camphor-10-sulfonic, capric. caproic. caprylic. cinnamic, citric. cyclamic. dodecylsulphuric, ethane-1.2-disulfonic. ethanesulfonic, 2-hydroxyethanesulfonic. ant, pounds, galaclam. gentiziiiic. glucoheptonic, D-gluconic,

glucuronic (eg D-glucuronic). glutamic (eg I -glutamic). o-oxoglutaric. glycolic. hipuma. hydrogen bromide. hydrochloric. hydrogen iodide. exceptional. lactic (e.g. ( • H..-lactic. l-DL-lactic), lactobionic. inaieinic. malic, (-)-l-malic, malonic. (.i )-DL-hademic, metathysulfonic. naphthalene!thonic (e.g. naphthalene-2-sulfonic). naphthalene-1..š-disulfonic. I-hydroxy-2-naphthoic. nicolinic. nitrogenous. oleic. orotic. oxalic, 1-amino-salicylic, lyocyanic, and acylated amino acids.

(02271 One particular group of salts consists of salts formed from acetic, hydrochloric, hydroiodic, phosphoric, nitrogenous, sulfuric, citric, lactic, succinic, maleic, malic, iseionic, phthymaric, benzenesylphonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valerian, acetic, propionic, butyric, malonic, glucuronic and lactobionic acid.

102281 The next group of acid addition salts includes salts formed from acetic acid. Adipine. ascorbic. aspartic. lemon. DL.-milky. ftimarn. gluconic. glucuronic. hippure. hydrochloric, glutamic, DL-malic. methanesulfonic, sebacic. stearic. succinic and tartaric acids.

|0229| The compounds of the invention can exist as inono- or di-salts depending on the pKa of the acid from which the salt is formed.

102301If the compound is anionic. or has a functional group that may be anionic (eg -COOI-I may be -COO"). then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to alkali metal ions, such as Na and K . alkaline earth metal cations, such as Ca" and Mg" . and other cations such as Al". Examples of suitable organic cations include, but are not limited to ammonium ion (ie, Nlf4") and substituted ammonium ions (eg, NH;R\ NH.R.i . \UR . NR, ).

(02311 Examples of some suitable substituted ammonium ions are those derived from the following: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolaniline, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine. as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH;).,'.

|0232| When compounds of formula (I) contain an amino function, they can form quaternary ammonium salts. for example, by reaction with an alkylating agent by methods well known to one skilled in the art. Such quaternary anionium compounds are within the scope of formula (I).

102331 The salts forming the compounds according to the invention are usually pharmaceutically acceptable salts. and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) "Pharmaceutically Acceptable Salts," J. Pharm. Sci., volume 66. p. I-19. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms, which can then be converted into pharmaceutically acceptable salts. Such pharmaceutically unacceptable salt forms, which may be useful, e.g. in the purification or isolation of compounds according to the invention, also form part of the invention.

102341 Compounds of formula (I) containing an amino function can also form N-oxides. Reference herein to compounds of formula (I) containing an amino function also includes the N-oxide.

|()235| When the compound contains several amino functions, then one or more nitrogen atoms can be oxidized to form the N-oxide. Specific examples of N-oxides are N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

|0236| N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a per-acid (eg, peroxycarboxylic acid), see for example. Advanced Organic Chemistrv, author

Jerrv March. 4th edition. Wiley Interscience. cheese. More precisely. N-oxides can be obtained by the procedure of Deadv, L W. (Svu. Comrn. (19771. 7. 509-514) in which the amino compound is reacted with m-chloroperoxybenzoic acid (MCPBA). For example, in an inert solvent. such as dichloromethane.

|0237| The compounds according to the invention can form solvates. for example. with water (ie hydrates) or with common organic solvents. As used herein, the term "solvate" refers to the physical association of a compound of the present invention with molecules of one or more solvents. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, solvai will be suitable for isolation, for example. when one or more solvent molecules are embedded in the crystal lattice of a crystalline solid. As used herein, the term "solvate" should include both solution-phase solvates and solvates that can be isolated. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol. ethanol. methanol, DMSO. ethyl acetate. acetic acid or ethanolamine and the like. The compounds according to the invention can exert their biological effects while in solution.

102381 Solvates are well known in pharmaceutical hernia. They may be important in processes for obtaining the substance (e.g., related to their purification, preservation of the substance (e.g., its stability), and ease of handling the substance, and are often formed as part of the isolation or purification step in chemical syntheses. One skilled in the relevant art can determine by standard and long-established techniques whether a hydrate or other solvate has formed under the isolation or purification conditions used to obtain a given compound. Examples of such techniques include thermogravimetric analysis (TGA), X-ray crystallography (eg, single-beam X-ray diffraction) and solid-state NMR (also known as Magic Angle Spinning NMR) are standard analytical tools for the trained chemist

MS.

|0239| Alternatively. one of ordinary skill in the art can deliberately form a solvate by applying crystallization under crystallization conditions that include the amount of solvent required for a particular solvate. The standard methods described above can then be used to determine if solvates have formed.

|0240|Furthermore, the compounds according to the present invention may have one or more polymorphic, amorphous or crystalline forms, and as such they should be included within the scope of the invention.

|02411 Compounds of formula (I) can exist in a number of different geometric isomeric and tautomeric forms, and the recitation of compounds of formula (I) includes all such forms. For the avoidance of doubt, if a compound can exist in one of several geometric isomeric or tautomeric forms, and only one is specifically described or shown, then all others are encompassed by formula (I).

[02421 Other examples of tautomeric forms include. for example. keto-, enol-, and enolate- forms, such as for example. the following tautomeric pairs; keto'enoi (shown below), imine enamine, amid'imino alcohol, amidine/amidine. nilrose/oxime. thioketone/enethiol. and nitro'aci-niiro.

|0243|If compounds of formula (1) contain one or more rural centers, and may exist in the form of two or more optical isomers, then reference to compounds of formula (I) includes all their optical isomeric forms (e.g.

cnantiomcrc. epinicre and diastereoisomers), either as individual optical isomers. or mixtures (eg, racemic mixtures) of two or more optical isomers. unless the context requires otherwise.

102441 Optical isomers may be characterized and identified by their optical activity (ie as + and - isomers. or (7i//r^mers) or may be characterized in terms of their absolute stereochemistry including the "K and S" nomenclature developed by Cahn. Ingold and Prelog. see Advanced Organic Chemistrv by Jerrv March. 4th ed. John Vilev & Sons. New York, 1992 pp. 109-14 and see also Ingold (1966) Int. Chem. 5, 385-415.

102451 Optical isomers can be separated using a number of different techniques including chiral chroma (chroma on a chiral support), and such techniques are well known to those skilled in the art.

|0246|As an alternative to chiral chromatography. optical isomers can be separated by forming diastereoisomeric salts with chiral acids, such as 1-f-sinic acid, (-)-pyroglutamic acid, (-)-di-to I uo and I- L- v i ii s ka acid, (^-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid. by separating the diastereomers by preferential crystallization and then dissociating the salt to give the individual enantiomer of the free base.

|0247|If compounds of formula (I) exist as two or more optically isomeric forms, then one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer. for example. in terms of biological activity. Accordingly, in the circumstances described, it may be desirable to administer only one of a pair of enantiomers, or only one of a plurality of diastereomers, as a therapeutic agent. Shondolome. the invention provides compositions containing a compound of formula (I) having one or more chiral centers, wherein at least 55% (e.g. at least 60%, 65%. 70%. 75%. 80%, 85%, 90%. or 95%) of the compound of formula (I) is present as a single optical isotherm (e.g. enantiomer or diastereoisomer). II to a general example of implementation. 99% or more (eg, on a dry basis) of the total amount of the compound of formula (I) may be present as only one optical isomer (eg, enantiomer or diastereoisomer).

)0248|Compounds according to the invention include compounds with one or more isotopic substitutions, and the mention of an individual element includes all isotopes of the element. For example. the mention of hydrogen in its scope includes 'H, \\ (D). and 'H (T). Similar breaks. mentions of carbon and oxygen include respectively i:C. 1 !C and l4C and '"O i<ls>O.

|0249| Isotopes can be radioactive or non-radioactive. In one embodiment according to the invention, the compounds do not contain radioactive isotopes. Such compounds are desirable for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

(02501Esters. such as carboxylic acid esters and acyloxy esters of compounds of formula (I) bearing a carboxylic acid group or a hydroxyl group are also covered by formula (I). In one embodiment of the invention, formula (I) includes within its scope esters of compounds of formula (i) bearing a carboxylic acid group or a hydroxyl group. In the following embodiment of the invention, formula (I) does not include within its scope esters of compounds of formula (I) which bear a carboxylic acid group or a hydroxyl group. Examples of ester groups include, but are not limited to, an ester substituent. -CHa.-C(=0)OC(CH,). -C("0)OPh. Examples of acyloxy irreversible esters and groups are represented by -OC("=0)R. wherein R is an acyloxy substituent. for example. C, - alkyl group. C1 >,, heterocyclyl group, or C1.

,,, an aryl group, and primarily a C 1 -, .: alkyl group. Preferred examples of acyloxy groups include. but are not limited to -

(H'( OK II. (aceioxy). OO OK'II t'll . -0('( t))C(CI I;);, -<>('( OlPh. and -OC< OK'HT'h.

|025l| Formula (I) also includes all possible existing polymorphic forms of the compound. solvates (eg, hydrates), complexes (eg, including complexes or clathrates with compounds such as cyclodextrins. or complexes with metals) of compounds and prodrugs of compounds. By "prodrugs" is meant. for example, bull) which compound which

is converted in vivo into a biologically active compound of formula (1).

|0252| For example, some prodrugs are esters of the active compound (eg, a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C( ())OR) is removed to give the active drug. Such esters can be formed by esterification. for example. of any carboxylic acid group <O OiOli) in the parent compound. with, where appropriate, prior to protection of any other reactive group present in the parent compound, followed by deprotection. if it was necessary.

|0253| Examples of such metabolically labile esters include those of the formula -C(=O)OR. where R is:

C 1-6 alkyl (eg -Me. -Eth. -nPr. -iPr. -nBu, -sBu. -iBu. -tBu):

C1-7ylaminoalkyl (eg aminoethyl; 2-(N,N-diethylamino)yl: 2-(4-morpholino)ethyl):

and acyloxy-C1.?alkyl (e.g. acyloxymethyl acyloxyethyl: pivaloyloxymethyl; acetoxymethyl; I-acetoxyethyl: l-( 1 -methoxy-l-methyl)ethylcarbonyloxyethyl; t-(benzoyloxy)ethic isopropoxycarbonyloxymethyl: I -isopropoxycarbonyloxyethyl; cyclohexyloxymethyl: cyclohexyloxy-carbonyloxymethyl;

I -cyclohexyloxycarbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl: I -(4-tetrahydropyranyloxy)carbonyloxyethyl.

(4-tetrahydropyranyl)carbonyloxymethyl: and I-(4-tetrahydropyranyl)carboyloxyethyl).

10254) Also. some prodrugs are activated enzymatically to produce the active compound. or a compound that, after the following hetnic reactions, gives an active compound (for example, as in antigen-directed enzyme prodrug therapy (ADEPT), in gene-directed enzyme prodrug therapy (GDI-.PT) and in ligand-directed enzyme therapy) prodru<g>therapv. I 11)1 PI : iul.). For example, the prodrug can be a sugar derivative or some other glycoside conjugate. or it could be an amino acid ester derivative.

|0255| Reference to "derivatives" is understood to include reference to their ionic forms, salts, solvates. isomers. tautomers, N-oxides. esters, prodrugs. isotopes and protected forms.

102561 According to one aspect of the invention, the compound delineated here or its salt, tautomer, is realized. N-oxide or solvate.

|02571 According to the following aspect of the invention there is provided a compound described herein or a salt or solvate thereof. |(I258| Listing of the compounds of formulas (I). (T). (Ta), (l'b). (I'ct and (l'd) and their subgroups which are defined here within their scope also includes salts or solvates or tautomers or N-oxides of these compounds.

Protein tyrosine kinases (PTKs)

|0259|The compounds of the invention described herein inhibit or modulate the activity of certain tyrosine kinase(s). and accordingly these compounds will be useful in the treatment or prophylaxis of disease states or disorders mediated by those tyrosine kinases. and especially with FGFR.

I (or R

102601 The fibroblast growth factor (FGF) family of protein tyrosine kinase (PI K) receptors regulates a range of diverse physiological functions including mitogenesis. wound healing. cell differentiation and angiogenesis. and development. The growth of normal and malignant cells, as well as their proliferation, are influenced by changes in the local concentration of FGFs. extracellular signaling molecules that also act as autocrine. and as paracrine factors. Aulocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state (Powvers. et al. (2000) Endocr. Relat. Cancer. 7. 165-197).

|026l|FGFs and their receptors are expressed at increased levels in several tissues and cell lines, and overexpression is thought to contribute to the malignant phenotype. Furthermore, several oncogenes are homologues of genes encoding growth factor receptors, and there is potential for aberrant activation of FGF-dependent signaling in human pancreatic cancer (Ozavva, et al. (2001). Teratog. Care inog. Mutagen.. 2 1. 27-14).

(02621 The two prototypical members are acidic fibroblast growth factor (aFGF or FGF1) and basic fibroblast growth factor (bFGF or FGF2). and to date at least twenty characteristic members of the FGF family have been identified. The cellular response to FGFs is mediated by four types of high-affinity fibroblast growth factor membrane protein-lyrosine-kinase receptors (FGFRs) numbered I through 4 (FGFRI to FGFR4) After ligand binding, the receptors dimerize and auto- or trans-lyse to specific cytoplasmic tyrosine residues to transmit an intracellular signal that ultimately regulates nuclear transcription factors.

102631 Disruption of the FGFR1 pathway should affect tumor cell proliferation, as this kinase is active in many tumor types, in addition to endothelial cell proliferation. Overexpression and activation of FGFR I in tumor-associated vasculature suggest a role for these molecules in tumor angiogenesis.

|0264|Illbroblast growth factor receptor 2 has a high affinity for acidic and or basic fibroblast growth factors. as well as for keratinocyte growth factor ligands. Fibroblast growth factor receptor 2 also propagates the potent osteogenic effects of FGF during osteoblast growth and differentiation. For mutations in the llbroblastic growth factor 2 receptor that lead to complex functional changes. has already been shown to induce abnormal ossification of the cranial sutures icraniosynostosis). implicating a major role of FGFR signaling in intramembranous bone formation. For example, in Apert (AP) syndrome, which is characterized by inverted ossification of the cranial sutures. most cases are associated with terminal mutations that cause increased function of the llbroblastic growth factor 2 receptor (Lemonnier. et al. (2001), .!. Bone Miner. Res.. 16. 832-845). In contrast, mutation screening in patients with syndromic craniosynostosis indicates that multiple recurrent FGFR2 mutations are responsible for severe forms of Pfeiffer syndrome (Lajetmie et al. European Journal of Human Genelics (2006) 14, 289-298). Specific FGFR2 mutations include W29()C. D32 I A. Y340C. C3 I2R, C342S. C342W. N549I I. K64 I R in FGFR2.

102651 Several serious abnormalities in human skeletal development, including A bead v. Crouzonov. Jackson-Weissov. Burr-Stevenson cutis neck. and Pfeiffer syndrome are associated with mutations in the llbroblast growth factor receptor 2. Most, if not all, cases of Pfeiffer syndrome (PS) are also caused by a de novo mutation of the llbroblast growth factor receptor 2 gene (Mevers. et al. (1996) Ani..1. Hum. Genet.. 58, 491-498: Plomp. et al. (1998) Am. J. Med. Genet., 75. 245-251). and it has recently been shown that mutations in the prescription of llbroblastic

of growth factor 2 violate one of the main rules of ligand specificity. Namely, two mutant splice forms of the fibroblast growth factor receptor. FGFR2c and F(<i>FR2b. acquire the ability to bind to and be activated by atypical FGF ligands. This loss of ligand specificity leads to aberrant signaling and suggests that the severe phenotypes of these disease syndromes result from ligand-dependent ectopic activation of the fibroblastic growth factor receptor 2 (Tu. et al. (2000). Proc. Natl. Acad. Sci. U.S.A.. 97. 14536-14541).

|0266| Genetic aberrations of the GFR3 receptor tyrosine kinase. such as chromosomal translocations or point mutations result in ectopically expressed or deregulated. constitutively active. FGFR3 receptors. Such abnormalities are associated with a subset of multiple myeloma and bladder cancer. hepatocellular carcinoma, oral squamous cell carcinoma and cervical carcinoma (Pcmers. C.J. (2000). el al.. F.ndocr. Rel. Cancer. 7. 165; Qiu. W. et. al. (2005). VVorkl Journal Gastroenterol, 11(34)). Accordingly. FGFR3 inhibitors would be useful in the treatment of multiple myeloma. and carcinoma of the bladder and cervix. FGFR3 is also overexpressed in bladder cancer. and especially invasive bladder cancer. FGFR3 is frequently activated by mutation in urothelial carcinoma (I'C) (Journal of Pathology (2007). 213(1). 91-98). Increased expression was associated with the mutation (85% of mutant tumors showed high expression), but also 42% of tumors with an undetectable mutation showed overexpression, including many muscle-invasive tumors.

102671 As such, compounds that inhibit FGFR will be useful for the realization of agents for preventing growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. It is therefore expected that the compounds will prove useful in the treatment or prevention of proliferative disorders, such as cancers. In particular, tumors with activating receptor tyrosine kinase mutants or overregulation of receptor tyrosine kinases may be particularly sensitive to inhibitors. It may also be found that for patients with activating mutants of any of the and/or form-specific RTKs discussed here, treatment with RTK inhibitors is not particularly beneficial.

|0268| I GFR4 overexpression is associated with poor prognosis in both prostate and thyroid cancers (Ezzat. S.. el al. (2002) The Journal of Clinical Investigation. 109. I; VVang el. (2004) Clinical Cancer Research, 10). The germline polymorphism (Glv388Arg) is associated with an increased incidence of lung, breast, colon and prostate cancer (VVang el al. (2004) Clinical Cancer Research. 10). In addition. a truncated form of FGFR4 (including the kinase domain) was also found to be present in 40% of pituitary tumors but not in normal tissue.

|0269| A recent study showed a relationship between FGFR1 expression and tumorigenicity in classic lobular carcinomas. CLCs represent 10-15% of all breast cancers and generally lack p53 and FIer2 expression. while maintaining estrogen receptor expression. Amplification of the 8p 12-pl 1.2 gene was demonstrated in -50% of CLC cases and was shown to be associated with increased expression of FGFRI. Preliminary studies with siRNA directed against FGFR1. or small molecule receptor inhibitors have shown that cell lines in which this amplification is carried out are particularly sensitive to the inhibition of this signaling pathway (Reis-Filho et al. (2006) Clin Cancer Res. 12(22); 6652-6662.

[02701 Rhabdomyosarcoma (RMS). the most common pediatric soft tissue sarcoma probably arises from abnormal proliferation and differentiation during skeletal myogenesis. FGFRI is overexpressed in primary rhabdomyosarcoma tumors and is associated with hypomethylation of 5' CpG genes and abnormal expression of AKTI, NOG. and BMP4 gene (Genes. Chromosomes & Cancer (2007). 46(1 l), 1028-1038).

|027l| Fibrotic lesions are a major medical problem resulting from abnormal or excessive deposition of fibrotic tissue. This appears in many diseases, including cirrhosis of the liver, glomerulonephritis. pulmonary phlebrosis.

systemic phlebrosis. rheumatoid arthritis, as well as natural wound healing processes. The mechanisms of pathological llhrosis are not fully elucidated, and are thought to be caused by several different cytokines (including tumor necrosis factor (TNF), fibroblast growth factors (FGF's), erythrocyte-derived growth factor (PDGF) and transforming growth factor beta (TFIFp) which are involved in fibroblast proliferation and deposition of extracellular matrix proteins (including collagen and fibronectin). This results in changes in tissue structure and function, as well as siedstveriom pathology.

|0272| Numerous preclinical studies have indicated an overregulation of fibroblast growth factors in preclinical models of pulmonary fibrosis (Inoue.el al.1907 & 2002: Barrios.ci ni.1997)). FGF [i I and PDGF have been shown to be involved in the fibrogenic process (reviewed by Atamas & White. 2003). and other published works suggest that the increase in FGF' and the consequent increase in fibroblast proliferation may be a reaction to increased TGFpl (Khalil.el al..2005). The potential therapeutic importance of this pathway in llbiotic conditions is suggested by the published clinical effect of pirfenidone (Arata.ci al., 2005) in idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (also called cryptogenic alveolar alveolitis) is a progressive condition involving scarring of the lungs. Gradually, the air chambers (alveoli) in the lungs are replaced by fibrous tissue, which becomes thicker, causing an irreversible loss of the tissue's ability to transport oxygen into the bloodstream. Symptoms of the condition include shortness of breath. chronic dry cough, fatigue, chest pain and loss of appetite, resulting in rapid weight loss. The condition is extremely serious, with an approximate mortality of 50°<> after 5 years.

Vascular endothelin growth factor (YFGFRi

|0273] Chronic proliferative diseases are often accompanied by profound augiogenesis. which may promote or maintain an inflammatory and/or pro-inflammatory state, or which leads to tissue destruction due to invasive proliferation of blood vessels (Folkman (1997), 79, 1-81: Folkman (1995). Nature Medicine. I. 27-31: Folkman and Shing (1992) J. Biol.Chem., 267, 10931).

102741 Angiogenesis is generally used to describe the development of new or embryonic blood vessels, or neovascularization. It represents a necessary and physiologically normal process by which the vasculature is established in the embryo. Angiogenesis generally does not occur in most normal adult tissues, with the exception of the site of ovulation. menstruation and wound healing. However, many diseases are characterized by abnormal and dysregulated angiogenesis. For example. in arthritis, new capillary blood vessels penetrate the joint and destroy the cartilage (Colville-Nash and Scott (1992). Anti. Rhum. Dis., 51, 919). In diabetes (and many different eye diseases), new blood vessels attack the macula or retina or other eye structures, and can cause blindness (Brooks, et al. (1994) Cell, 79, 1157). The process of atherosclerosis is associated with angiogenesis (Kahlon. et al. (1992) Can..1. CardioL 8. 60). Tumor growth and metastasis have been found to be dependent on angiogenesis (Folkman (1992). Cancer Biol. 3. 65: Denekamp. (1993) Bi'. J. Rad.. 66,181; Fidler and Fllis (1994), Cell, 79,185).

|0275| The recognition of the involvement of angiogenesis in most diseases was accompanied by research aimed at the identification and development of inhibitors of angiogenesis. These inhibitors are generally classified according to their response to specific targets in the angiogenesis cascade. such as activation of endothelial cells with an angiogenic signal: synthesis and release of degradative enzymes: migration of endothelial cells: proliferation of endothelial cells: and formation of capillary tubules. Therefore, angiogenesis occurs at many stages and attempts are being made to discover and develop compounds that act to block angiogenesis at these various stages.

|0276| There are publications explaining that they are inhibitors of angiogenesis. acting by different mechanisms, useful in diseases such as cancer and metastases (0" Reiily. et al. (1994) Cell. 79. 315: Ingber. et al. (1990) Nature,

348. 555). eye diseases (Friedlander. et al. (1005) Science. 270.1500). arthritis (Peacock. et al. (1992)..). Exp. Med.. 175. I 135; Peacock et al. (1995). Cell. Imnum.. 160,178) and hemangioma (Taraboletti. et al. (1995) J. Natl. Cancer Inst.. 87. 293).

|0277| Receptor tyrosine kinases (RTKs) are important in transmitting biochemical signals across the cell membrane. Characteristically, these transmembrane molecules consist of an extracellular ligand-binding domain linked by a segment in the cell membrane to an intracellular tyrosine kinase domain. Ligand binding to the receptor results in stimulation of receptor-associated tyrosine kinase activity. which leads to the phosphorylation of tyrosine residues on both prescription and other intracellular proteins, which further leads to various cellular reactions. At least nineteen distinct RTK subfamilies have been identified to date. which are defined by amino acid sequence homology.

|0278| Vascular endothelial growth factor (VECiF). polypeptide. is a mitogen for endothelial cells and viiroi stimulates angiogenic responses and nr/m VEJE is also associated with inappropriate angiogenesis (Pinedo. H.M.. et al.

(2000). The Oncologist. 5(90001). 1-2). VEGFR(s) are protein tyrosine kinases (PIKs). PIKs catalyze the phosphorylation of specific tyrosine residues in proteins involved in cell function by regulating growth. cell survival and differentiation (Vilks. A.F. (1990). Progress in Growth Factor Research. 2. 97-1 and I; Courtneigge, S.A. (1993) Dev. Supp.I. 57-64; Cooper. J.A. (1994), Semin, Cell Biof. 5(6). 377-387: Paulson. R.F. (1995). Scmin. Immunol, 7(4), 267-277: Curr. Immunol.. 394-401. |0279] Three PTK receptors for VI Gf have been identified: \ I GI R -1 (l-lt-1): VEGFR-2 (lik -1 or KDR) and VEGFR-3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction (Mustouen. 1, et al.. (1995).. 1. Cell BioL 129, 895-898). |0280| Of particular interest is VEGFR-2, which is a PI K transmembrane receptor expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression can be constitutive of tumor cells and can also be upregulated in response to certain stimuli. One such stimulus is hypoxia. where VEGF expression is upregulated in both tumor and associated host tissues. VEGF ligand activates VEGFR-2 by binding to its extracellular VEGF binding site. This leads to dimerization of VEGFRs receptors and autophosphorylation of tyrosine residues on the intracellular domain of VEGFR-2 kinase. The kinase domain functions to transfer phosphate from ATP to tyrosine residues, thereby providing binding sites for signaling proteins downstream of VEGFR-2. Which finally leads to the initiation of angiogenesis (McMahon, G. (2000). The Oncologist. 5(90001), 3-10).

10281) Inhibition of the VEGFR-2 kinase domain binding site would block phosphorylation of tyrosine residues and serve to terminate the initiation of angiogenesis.

(02821 Angiogenesis is a physiological process of new blood vessel formation mediated by various cytokines called angiogenic factors. Although its potential paleolisiological role in solid tumors has been comprehensively studied for more than 3 decades, the involvement of angiogenesis in lyronic lymphocytic leukemia (CEE) and other malignant hematological disorders has only recently been recognized. Elevated levels of angiogenesis have been documented by various experimental methods in both bone marrow and lymph nodes. in patients with CEE. Although the role of angiogenesis in the pathophysiology of this disease has yet to be fully elucidated, several angiogenic factors have been shown to play a role in the progression of the disease. This suggests that VEGFR inhibitors may also be useful in patients with CEL.

|0283|For a tumor mass to grow beyond a critical size, it must develop an accompanying vasculature. It has been proposed that targeting the tumor vasculature limits tumor expansion and may be useful in cancer therapy. Observations of tumor growth have indicated that small tumor masses can persist in tissue without tumor-specific vasculature. Growth arrest of non-vascularized tumors is attributed to the effects of hypoxia in the tumor center. More pro-angiogenic and anti-angiogenic factors have recently been identified and have led to the concept of "angiogenic modulation", a process in which disruption of the normal ratio of angiogenic stimulators and inhibitors in the tumor mass enables autonomous vascularization. Angiogenic modulation appears to be governed by the same genetic factors that drive malignant conversion: activation of oncogenes and loss of tumor suppressor genes. Several growth factors act as positive regulators of angiogenesis. Among them are primary vascular endothelial growth factor (VEGF). basic fibroblast growth factor tbf-dl-s. and angiogenin. Proteins such as thrombospondin (Tsp-I). angiostatin. and endostatin function as negative regulators of angiogenesis.

|0284| Inhibition of VEGFR2. but not VEGFRI significantly disrupts angiogenic modulation, ongoing angiogenesis, and initial tumor growth in a mouse model. In late stage tumors, phenotypic resistance to VEGFR2 blockade appears, since after an initial period of growth suppression, tumors begin to grow again during treatment. This resistance to VEGF blockade includes the reactivation of tumor angiogenesis. independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family. These other proangiogenic signals are functionally involved in revascularization and regrowth of tumors in the evasive phase, as FGF blockade attenuates progression in contrast to VEGF inhibition. Inhibition of VEGFR2. but not VEGFRI significantly disrupts angiogenic modulation, ongoing angiogenesis, and initial tumor growth. Late-stage LJ tumors show phenotypic resistance to VEGFR2 blockade, as tumors regrow during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis. independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family. These other proangiogenic signals are functionally involved in the revascularization and regrowth of tumors in the evasive phase. since FGF blockade reduces progression unlike VEGF inhibition.

|0285|There have been previous reports that FGF-trap adenovirus binds and blocks various ligands of the FGF family, including FGFI. FGF3, FGF7. and FGF 10. thereby effectively inhibiting angiogenesis in vitro and in vivo. Indeed, the addition of FGF-trap treatment during the regrowth phase in a mouse model produced a significant reduction in tumor growth compared to anti-VEGFR2 alone. This decrease in tumor burden was accompanied by a decrease in angiogenesis, which was observed in the form of a reduced density of intratumor blood vessels.

|0286|Batchelor et al. (Batchelor et al.. 2007. Cancer Cell. 11(1). 83-1>5) provide evidence for normalization of glioblastoma blood vessels in patients treated with the pan-VEGF receptor alyrosine kinase inhibitor. AZD2I7I. in phase 2 of the study. The rationale for using AZD2I7I was based in part on reports showing a reduction in perfusion and vessel density in an in vivo model of breast cancer (Miller et al. 2006. Clin. Cancer Res. 12. 281-288). In addition. using an orthotopic glioma model, the optimal time frame for the administration of anti-VEGFR2 antibodies in order to achieve a synergistic effect with radiation was previously identified. During the normalization time interval, the oxygen supply was improved. increased perieit coverage. and overregulation of angiopoietin-1, which led to a decrease in interslicial pressure and permeability within the tumor (\V inkler et al.. 200«). Cancer Cell 6. 553-563). The time interval for normalization can also be quantified using magnetic resonance imaging (MRI) using MRI gradient echo. spin echo. and contrast enhancement to sc measure blood volume. relative size of blood vessels and vascular permeability.

102871 The authors showed that progression on A7.D2 I 7 I treatment was associated with an increase in CECs. SDFI, and FGF2. while progression after drug discontinuation is consistent with an increase in circulating progenitor cells (CPCs) and plasma FGF2 levels. The increase in SDFI and 1-'GI 2 levels in plasma was consistent with MRI measurements. which showed an increase in the relative density and size of blood vessels. Accordingly. MRI determination of blood vessel normalization in combination with circulating biomarkers provides an effective means of determining response to antiangiogenic agents.

PDG FR

|0288| A malignant tumor is a product of uncontrolled cell proliferation. Cell growth is controlled by a delicate balance between growth-promoting factors and growth-inhibiting factors. In normal tissue, the production and activity of these factors result in the growth of differentiated cells that grow in a controlled and regulated manner that maintains normal organ integrity and function. A malignant cell is out of control: the natural balance is disturbed (through a multitude of mechanisms) and unregulated, abnormal cell growth occurs, a growth factor of importance in tumor development is the platelet-derived growth factor (PDGF) which comprises a family of peptide growth factors that signal through the tyrosine kinase receptor (PDGFR) on the cell surface and stimulate various cellular functions, including growth, proliferation and differentiation. PDGF expression has been demonstrated in a number of different solid tumors, including glioblastomas and prostate carcinomas. The tyrosine kinase inhibitor imatinib mesylate. which has the chemical name 4-|(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-ylpyridine! jaminoJ-phenyl|benzamide methanesulfonate, blocks the activity of Bcr-Abl oncoprotein and receptor tyrosine kinase on the surface of c-K.il cells. and as such is approved for the treatment of (ironic myeloid leukemia and gastrointestinal stromal tumors. Imatinib mesylate is also a potent inhibitor of PDGFR kinase and is currently in trials for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme. which is based on evidence that in these diseases activating mutations in PDGFR. In addition. sorafenib (BAY 43-9006) which has the chemical name 4-(4-(3-(4-chloromethyl)phenyl)thenoxy)-N2-methylpyridine-2-carboxamide targets both the Raf signaling pathway to inhibit cell proliferation and the VKGFR signaling cascade to inhibit tumor angiogenesis. Sorafenib is being investigated for the treatment of several cancers, including liver and kidney.

|0289| There are conditions that are dependent on PDGFR activation such as hypereosinyl syndrome. PDGFR activation has been associated with other malignancies. which include chronic myeloid leukemia (CMML). In another disorder, dermatofibrosarcoma protuberans. intiltrative tumor of the skin. reciprocal translocation. which includes the gene encoding PDGF-B ligand. results in constitutive secretion of the chimeric ligand and activation of the receptor. Imatinib. which is a known PDGFR inhibitor. has activity against all three of these diseases.

Advantages se.ektiv uog iub i bi to ra

|0290| The development of FGFR kinase inhibitors with a differentiated selectivity profile provides a new opportunity for the application of these targeted agents in patients from subgroups whose diseases are triggered by FGFR deregulation. Compounds that exhibit reduced inhibitory activity on additional kinases. and especially on VEGFR2 and PDGFR-beta, provide the possibility to achieve a differentiated adverse effect or toxicity profile and as such provide more effective treatment of these indications. VFGFR2 and PDGFR-beta inhibitors are associated with toxicities, such as hypertension or edema, respectively. In the case of VEGFR2 inhibitors, this hypertensive effect, which is often dose-limiting, may be contraindicated in certain patient populations and requires clinical application.

Biological activity and therapeutic applications

Compounds of the invention, and subgroups thereof, have fibroblast growth factor receptor (FGFR) inhibitory or inducing activity and/or vascular endothelial growth factor receptor (VI dl R) inhibitory or modulating activity, and/or platelet-derived growth factor receptor (PDGFR) inhibitory or inducing activity, and will be useful in the prevention or treatment of diseases or conditions herein. described. In addition. compounds of the invention, and subgroups thereof, will be useful for the prevention or treatment of kinase-mediated diseases or conditions. A reference to the prevention or prophylaxis or treatment of a disease or condition, such as cancer, includes within its scope the alleviation or reduction of the incidence of cancer.

|0292|When used herein, the term "modulation" is applied to kinase activity. sky to define the change in the level of protein kinase biological activity. Accordingly. modulation includes physiological changes that affect an increase or decrease in the activity of the relevant protein kinase. In the latter case, modulation can be described as "inhibition". Modulation can be induced directly or indirectly and can be mediated by any mechanism and at any physiological level including, for example. the level of gene expression (including, for example. transcription, translation and/or post-translational modification), at the level of expression of genes encoding regulatory elements that act directly or indirectly on the levels of kinase activity. Accordingly. modulation may imply increased/repressed expression or over- or under-expression of the kinase. including gene amplification (i.e., multiple copies of a gene) and/or increased or decreased expression due to a transcriptional effect, as well as hyper- or hypo-)activity and (de(activation) of protein kinases. i.e. kinases (including (de(activation) by imitation, i.e. mutations. When used herein, then the terms "modulated." "modulating" and "modulating" should be interpreted accordingly).

|02931 When used herein, then the term "mediates", as used e.g. in connection with a kinase described herein (and applied. e.g. to various physiological processes, diseases, conditions, disorders, therapies, treatments or interventions) should be used in a limiting sense, so that the various processes, diseases, conditions, disorders, treatments and interventions to which it applies represent those in which the kinase plays a biological role. In cases where this term is applied to a disease, condition or disorder, then the biological role played by the kinase may be direct or indirect and may be necessary and/or sufficient for the manifestation of symptoms of the disease, condition or disorder (or its etiology or progression). Accordingly. kinase activity (and in particular abnormal levels of kinase activity, e.g. overexpression of a kinase) need not be the underlying cause of a disease, condition or disorder: instead, kinase-mediated diseases, conditions or disorders are rather considered to include those with multifactorial etiologies and complex progressions, in which the kinase in question is only partially involved. In cases where this term applies to treatment. prophylaxis or intervention, the role played by the kinase may be direct or indirect and may be necessary and/or sufficient to effect treatment, prophylaxis or intervention outcomes. Accordingly. a kinase-mediated disease, condition or disorder includes the development of resistance to any particular cancer drug or treatment.

|0294| According to break, for example. It is contemplated that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.

|0295|More precisely, the compounds of formula (I) and their subgroups are FGFR inhibitors. For example. compounds according to the invention have activity against FGFRI. FGFR2. FGFR3. and or FGFR4. and especially against FGFRs selected from FGFRI, FGFR2 and FGFR3.

102961 Preferred compounds are compounds that inhibit one or more FGFRs selected from FGFRIs. FGFR2 and FGFR3, and also FGFR4. Preferred compounds according to the invention are those having IC > values of less than 0.4 µM. |0297| The compounds of the invention also have anti-VEGFR activity.

|0298| The compounds of the invention also have activity against PDGFR kinases. The compounds are particularly inhibitors of PDGFR and. for example. inhibit PDGFR A and/or PDGFR B.

10299] In addition, many compounds of the invention exhibit selectivity for FGFR I, 2, and or 3 kinase. and/or FGFR4 compared to VF.GFR (and especially VF.G1 R2) and or PDGFR and such compounds represent one preferred embodiment of the invention. The compounds particularly exhibit selectivity towards VP.GFR2. For example. many compounds of the invention have IC* values against FGFRI. 2 and or 3 and or I GFR4 which are between tenfold and one hundredfold of IC*, against VEGFR (and especially VEGFR2) and or PDGFR B. Especially preferred compounds according to the invention have at least 10 times greater activity against FGFR, and especially against FGFRI. FGFR2. FGFR3 and/or FGFR4 than against VEGFR2. Even more preferably, the compounds of the invention have at least 100-fold greater activity against FGFR or inhibition thereof, particularly against FGFRI. FGFR2. FGFR3 and or both GFR4 than against VEGFR2. This can be determined using the methods described here.

|0300| As a consequence of their activity in modulating or inhibiting FGFR. VEGFR and or PDGFR kinases, the compounds will be useful in providing a means of inhibiting the growth or inducing apoptosis of neoplasia, particularly by inhibiting angiogenesis. It is therefore expected that the compounds will prove useful in the treatment or prevention of proliferative disorders such as cancers. In addition. compounds of the invention may be useful in the treatment of diseases in which proliferation is impaired. upoptosis or differentiation.

|030l]Especially tumors with activating VEGFR mutants or VEGFR overregulation. as well as patients with elevated levels of serum lactal dehydrogenase may be particularly sensitive to the compounds of the invention. Patients with activating mutants of any of the isoform-specific R 1 Xs discussed herein may also be particularly beneficial to treatment with compounds of the invention. For example. overexpression of VEGFR in acute leukemia cells, where the clonal progenitor may express VEGFR. Also specific tumors with activating mutants or upregulation or overexpression of any of the FGFR isoforms. such as FGFRIs. FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to the compounds of the invention and accordingly. patients with such particular tumors as discussed herein may also be particularly beneficial to treatment with compounds of the invention. It may be desirable when the treatment is related to or directed to a mimic form of one of the tyrosine kinase receptors, as discussed herein. Diagnosis of tumors with such mutations could be performed using techniques known to those skilled in the art and as described herein, such as RTPCR and

ITSH

|0302| Examples of cancers that can be treated (or inhibited) include. but are not limited to the following: cancer, for example, bladder cancer. breast, colon (eg, colorectal cancers, such as colonic adenocarcinoma and colonic adenoma), kidney, epidermis. liver, lungs, such as. for example. adenocarcinoma, small cell lung cancer and non-small cell lung cancer, esophagus, gall bladder. ovaries, pancreas, e.g. exocrine carcinoma of the pancreas, stomach, cervix, endometrium. thyroid, prostate, or skin. for example. squamous cell carcinoma, hematopoietic tumor of the lymphoid lineage, such as for example. leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma. T-cell lymphoma. Hodgkin's lymphoma. non-l Lodzkin's lymphoma, hairy cell lymphoma, or Burkill's lymphoma: a hematopoietic tumor of the myeloid lineage. as they are. for example. leukemia, acute and chronic myelogenous leukemia, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia: multiple myeloma; follicular thyroid cancer: a tumor of mesenchymal origin, such as for example. fibrosarcoma

or rhabdomyosarcoma: a tumor of the central or peripheral nervous system, such as for example. astrocytoma. neuroblastoma. glioma or schwannoma: metanoma; seminoma: teratocarcinoma: osteosarcoma: xeroderma pigmentosum; keraloktantoma: follicular cancer of the thyroid gland: or Kaposi's sarcoma.

(03031 Certain cancers are resistant to treatment with certain courses. This may be due to the type of tumor or may be due to treatment with a compound. In general, the designation of multiple myeloma includes bortezomib-sensitive multiple myeloma or refractory multiple myeloma. Similarly, the designation of ironic myelogenous leukemia includes imitinib-sensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia. Myelogenous leukemia is also known as chronic myeloid leukemia, (ironic granulocytic leukemia or CML. Similarly, acute myelogenous leukemia is also called acute nieloblastic leukemia, acute granulocytic leukemia, acute nonlymphocytic leukemia, or AMf.

|0304|The compounds of the invention can also be used in the treatment of hematopoietic diseases with abnormal cell proliferation, whether premalignant or stable, such as myeloproliferative diseases. Myeloproliferative diseases ("MPDs") are a group of bone marrow diseases. in which an excess of cells is created. They are related and can develop into myelodysplastic syndrome. Myeloproliferative diseases include the following: polycythemia\era. essential thrombocyemia and primary myelophtbrosis.

103051 Accordingly. in a pharmaceutical composition, and for a compound of the present invention for use in the treatment of a disease or condition involving abnormal cell growth, the disease or condition involving abnormal cell growth in one example being cancer.

(03061Other T cell lymphoproliferative diseases include those derived from natural killer cells. The term B-cell lymphoma includes diffuse large B-cell lymphoma

|03071 In addition the compounds according to the invention can be used for gastrointestinal cancer (also known as stomach cancer) e.g. for gastrointestinal stromal tumors. Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract, including the esophagus, stomach, liver, biliary system, pancreas, intestines. and anus.

|0308|The next example of a tumor of mesenchymal origin is Ewing's sarcoma.

|0309|Accordingly. in pharmaceutical compositions and for a compound of the present invention for use in the treatment of a disease or condition comprising abnormal cell growth, said disease or condition comprising abnormal cell growth in one exemplary embodiment is cancer.

[03101Special subsets of cancer include multiple myeloma. bladder cancer. cervix, prostate and thyroid gland. lungs, breast and colon.

|03111 The next subset of cancers includes multiple myeloma, bladder cancer. hepatocellular carcinoma, oral squamous cell carcinoma and cervical carcinoma.

103121 It is further presented that a compound according to the invention that has KiPR inhibitory activity, such as FGFRI inhibitory activity, will be particularly useful in the treatment or prevention of breast cancer, especially classical lobular carcinoma (CLC).

f0313) Since the compounds according to the invention have FGFR-I activity, they will also be useful in the treatment of prostate cancer or pituitary cancer.

|03141 Compounds of the invention as FGFR inhibitors are particularly useful in the treatment of multiple myeloma. mieloprol of iterative disorders, endometrial cancer. prostate cancer, bladder cancer. lung cancer, ovarian cancer, breast cancer, stomach cancer, colorectal cancer. and oral squamous cell carcinoma.

|03I5|The following cancer subsets are multiple myeloma. endometrial cancer. bladder cancer. cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer and thyroid cancer.

(03161 Compounds according to the invention are particularly useful in the treatment of multiple myeloma (and especially multiple myeloma with 1(4:14) translocation or overexpression of FGFR3i). prostate cancer (hormone-refractory prostate cancer), endometrial cancer (and especially endometrial tumors with activating mutations in FGFR2) and breast cancer (and especially lobularnth breast cancer).

1031T| The compounds are particularly useful for the treatment of lobular carcinomas, such as (I.G (classic lobular carcinoma).

|0318|Since the compounds have activity against FGFR3. then it will be useful in the treatment of multiple myeloma and bladder cancer.

|03I9|The compounds are particularly useful for the treatment of multiple myeloma positive for the t(4;]4) translocation.

103201 As the compounds have activity against FGFR2. then it will be useful in the treatment of endometrial, ovarian, gastric and colorectal cancer. FGFR2 is also overexpressed in epithelial ovarian cancer, and therefore the compounds of the invention may be specifically useful in the treatment of ovarian cancer, such as epithelial ovarian cancer.

|0321|Compounds of the invention may also be useful in the treatment of tumors previously treated with a VEGFR2 inhibitor or VEGFR2 antibody (eg, Avastin).

10322[The compounds of the invention may be particularly useful in the treatment of VEGFR2-resistant tumors. VEGFR2 inhibitors and antibodies are used in the course of thyroid and renal cell carcinomas, therefore the compounds of the invention may be useful in the treatment of VEGFR2-resistant thyroid and renal cell carcinomas.

|0323|Cancers can be cancers that are sensitive to inhibition of one or more KGFRs selected from the FGFRIs. FGFR2. FGFR3. FGFR4. as they are. for example. one or more FGFRs selected from FGFR I. FGFR2 or FGFR3.|0324|Is any cancer sensitive to FGFR inhibition. VEGFR or PDGFR signaling or not. can be determined by the cell growth assay described below or by the method described in the section entitled "Diagnostic Methods".

|0325|It is further contemplated that the compounds of the invention, and particularly those compounds having FGFR, VEGFR or PDGFR inhibitory activity, will be particularly useful in the treatment or prevention of cancers of the type associated with or characterized by the presence of elevated levels of FGFR. VEGFR or PDGFR. as they are. for example, the cancers referred to in this context in the introductory section of this application.

|0326|It has been discovered that some FGFR inhibitors can be used in combination with other anticancer agents. For example. it may be useful to combine an inhibitor that induces apoptosis with another agent that works by a different mechanism to regulate cell growth, thereby treating two hallmarks of cancer development. Examples of such combinations are listed below.

|()3271 It is also contemplated that the compounds of the invention will be useful in the treatment of other disorders resulting from proliferative disorders. such as type II or non-insulin-dependent diabetes mellitus. autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as Alzheimer's, motor neuron diseases, progressive supranuclear palsy, corticobasal degeneration and Pick's disease, for example. autoimmune diseases and inborn diseases.

|0328|One subset of diseases and conditions where the compounds of the invention are predicted to be useful are inflammatory diseases, cardiovascular diseases and wound healing.

|0329|It also knew that FGFR. VEGFR and PDGFR have a role in apoptosis. angiogenesis. proliferation. differentiation and transcription and therefore the compounds of the invention may also be useful in the treatment of the following

diseases other than cancer: chronic inflammatory diseases, for example. systemic hippus erythematosus. autoimmune-mediated glomerulonephritis. rheumatoid arthritis, psoriasis. inflammatory bowel disease, autoimmune diabetes mellitus. eczematous hypersensitivity reactions, asthma. COPD. rhinitis. and upper respiratory tract disease: cardiovascular disease, for example. cardiac hypertrophy, restenosis. atherosclerosis; neurodegenerative disorders, for example. Alzheimer's disease, AIDS-related dementia. Parkinson's disease, amyotrophic lateral sclerosis, relinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic injury associated with myocardial infarction. stroke and reperfusion injury, arrhythmia, atherosclerosis. toxin-induced or alcohol-related liver diseases, hematological diseases, for example. (ironic anemia and aplastic anemia: degenerative diseases of the musculoskeletal system, eg. osteoporosis and arthritis, aspirin-sensitive rhinosinusitis. cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

103301 In addition, FGFR2 mutations are associated with several serious abnormalities in human skeletal development, and therefore the compounds of the invention may be useful in the treatment of abnormalities in human skeletal development, including abnormal ossification of cranial sutures (craniosynostosis). Apert (AP) syndrome; Crouzon syndrome. Jackson-Weiss syndrome, Burr-Stevenson cutis gvrate syndrome, and Pfeiffer syndrome.

It is further contemplated that compounds of the invention having FGFR inhibitory activity, such as FGFR2 or FGFR3 inhibitory activity, will be particularly useful in the treatment or prevention of skeletal diseases. Special diseases of the skeleton are achondroplasia or thanatophoric dwarfism (also known as kaolanatophoric dysplasia).

103321 It is further contemplated that a compound of the invention having FGFR inhibitory activity, such as FGFRI, FGFR2 or FGFR3 inhibitory activity, will be particularly useful in the treatment or prevention of pathologies in which progressive fibrosis is a symptom. Fibrotic conditions in which the compounds of the invention may be useful in the treatment include diseases in which there is abnormal or excessive deposition of librous tissue, for example. in liver cirrhosis, glomerulonephritis. pulmonary fibrosis. systemic fibrosis. rheumatoid arthritis, as well as the natural wound healing process. The compounds of the invention may be particularly useful in the treatment of pulmonary fibrosis. and especially idiopathic pulmonary fibrosis.

103331 Overexpression and activation of FGFR and VI-GFK in the tumor-associated vasculature also suggest that the role of the compounds of the invention is in preventing and interrupting the initiation of tumor angiogenesis. The compounds of the invention may be particularly useful in the treatment of cancer. metastasis, leukemia, such as CLL. eye diseases, such as age-related macular degeneration, and especially the wet form of age-related macular degeneration, ischemic proliterative retinopathy. such as retinopathy of prematurity (ROP) and diabetic retinopathy. reuniatoid arthritis and hemangioma.

f03341 Since the compounds of the invention inhibit PDGFR. they may also be useful in the treatment of several types of tumors and leukemias including glioblastomas, such as glioblastoma multiforme. prostate cancers, gastrointestinal stromal tumors, liver cancer, kidney cancer, chronic myeloid leukemia, chronic myelomonocytic leukemia (CMML), as well as hypereosinolar syndrome, a rare proliferative hematologic disorder, and dermatofibrosarcoma protuberans, an invasive skin tumor.

|0335|Activity of compounds according to the invention as FGFR I-4 inhibitors. V'f. GPR and or PDGFR A B can be measured using the assays listed below in the examples and the level of activity exhibited by a given compound can be defined in terms of CM values. Preferred compounds according to the present invention are compounds having IC values of less than 1 µM, more preferably less than 0.1 µM.

|0336| The invention provides compounds that have FGFR inhibitory or anti-inflammatory activity, and are expected to be useful in the prevention or treatment of diseases or conditions mediated by FGFR kinase(s).

|0337| In one exemplary embodiment, a compound delineated herein for use in therapy is provided. In the following exemplary embodiment, a compound disclosed herein for use in the prophylaxis or treatment of an FGFR kinase-mediated disease or condition is provided.

|0338| That's right. for example. demonstrated that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer. Accordingly. in the following exemplary embodiment, a compound defined herein for use in the prophylaxis or treatment of cancer is provided.

|0339| Accordingly, according to one aspect, the invention is realized by the use of the compound for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition mediated by FGFR kinase. and the compound has formula (I) as defined herein.

10340) In one exemplary embodiment, the use of a compound defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition described herein is realized.

103411 In the following exemplary embodiment, the use of the compound described herein for the manufacture of a drug for the prophylaxis or treatment of cancer is realized.

|0342| Accordingly. the subject description of the invention, among other things, describes

a compound of formula (I) for use in a method for the prophylaxis or treatment of an FGFR kinase mediated disease or condition, the method comprising administering to a subject in need thereof a compound of formula (I) as defined herein.

|0343| In one exemplary embodiment, a compound of formula (I) is provided for use in a method of prophylaxis or treatment of a disease or condition described herein, which method comprises administering to a subject in need thereof a compound of formula (i) described herein.

103441 In the following exemplary embodiment, a compound of formula (!) is provided for use in a method of prophylaxis or treatment of cancer, which method comprises administering to a subject in need thereof a compound of formula (I) described herein. 103451 A compound of formula (I) for use in a method of ameliorating or reducing the incidence of an FGFR kinase mediated disease or condition. which method comprises administering to a subject in need thereof a compound of formula (I) described herein.

10346| A compound of formula (I) for use in a method of inhibiting FGFR kinase. wherein said method comprises contacting the kinase with a kinase-inhibiting compound of formula (I) as defined herein.

|0347| A compound of formula (I) for use in a method of modulating a cellular process (eg, cell proliferation) by inhibiting FGFR kinase activity using a compound of formula (1) as defined herein.

|0348| A compound of formula (I) as defined herein for use as a modulator of a cellular process (eg, cell proliferation) by inhibiting FGFR kinase activity.

10349| Compounds of formula (1) defined herein for use as a modulator (eg, inhibitor) of FGFR.

|0350| Use of a compound of formula (I) as defined herein for the manufacture of a medicament for modulating (eg, inhibiting) FGFR activity.

103511 Use of a compound of formula (I) as defined herein for the manufacture of a medicament for modulating a cellular process (eg. cell proliferation) by inhibiting FGFR kinase activity.

103521 Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition characterized by overregulation of FGFR kinase (eg, FGFRI or FGFR2 or FGFR3 or FGFR4). |0353| Use of a compound of formula (1) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of cancer. where the cancer is one of those characterized by overregulation of FGFR kinase (eg FGFRI or FGFR2 or FGFR.i or FGFR4).

|()354| Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of cancer in a patient selected from a subpopulation having genetic aberrations of FGFR3 kinase.

103551 Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of cancer in a patient diagnosed with it. and which represents part of the subpopulation that has genetic aberrations of FGFR3 kinase.

|0356| A compound of formula (I) for use in a method for the prophylaxis or treatment of a disease or disorder characterized by upregulation of FGFR kinases (eg, FGFRI or FGFR2 or FGIR3 or I GFR4). which method comprises providing a compound of formula (I) as defined herein.

103571 A compound of formula (I) for use in a method for ameliorating or reducing the incidence of a disease or condition characterized by overregulation of FGFR kinases (eg, FGFRI or FGFR2 or FGFR3 or FGFR4), which method comprises administering a compound of formula (I) as defined herein.

|0358| A compound of formula (I) for use in a method for the prophylaxis or treatment of (or alleviating or reducing the incidence of) cancer in a patient suffering from or suspected of suffering from cancer; wherein the method comprises (i) subjecting the patient to a diagnostic test to determine whether the patient has genetic aberrations of the FGFR3 gene; and (ii) if the patient has said variant, then the patient is administered a compound of formula (I) as defined herein which has inhibitory activity for FGFR3 kinase.

J03591 A compound of formula (I) for use in a method for the prophylaxis or treatment (or amelioration or reduction in incidence) of a disease or condition characterized by overregulation of an FGFR kinase (eg, FGFRI or FGFR2 or FGFR3 or FGFR4); wherein the method comprises (i) subjecting the patient to a diagnostic test to detect a marker characteristic of FGFR kinase upregulation (eg, FGFRI or FGFR2 or FGFR3 or FGFR4) and (ii) where the diagnostic test is indicative of FGFR kinase upregulation. and thereafter administering to the patient a compound of formula (I) as defined herein having inhibitory activity for Idi R kinases.

|0360|In one exemplary embodiment, the disease mediated by FGFR kinases is an oncological disease <eg. cancer). In one exemplary embodiment, the disease mediated by FGFR kinases is not an oncological disease (eg, any disease described herein excluding cancer). In one exemplary embodiment, a disease mediated by FGFR kinases is a condition described herein. In one exemplary embodiment, disease mediated by FGFR kinases is the skeletal transmission described herein. Specific abnormalities in the development of the human skeleton include abnormal ossification of the cranial sutures (craniosynostosis). Apert (AP) syndrome. Crouzon syndrome. Uzhekson-Weiss syndrome, Burr-Stevenson cutis gyratc syndrome. Pfeiffer syndrome, achondroplasia, and thanatophoric dwarfism (also known as thanatophoric dysplasia).

MiUira^Jim„a?e

|036l|Drug-resistant kinase mutations may occur in patient populations treated with kinase inhibitors. They appear, in part, in regions of the protein that bind or interact with the specific inhibitor used in therapy. Such mutations decrease or increase the capacity of the inhibitor to bind and to inhibit

specific kinase. This can occur at any amino acid residue that interacts with the inhibitor or is important to support the binding of said inhibitor to the target. The mutation is unlikely to affect the inhibitor binding to the target kinase without the need to interact with the mimic amino acid residue and it will remain an effective inhibitor of the enzyme (Charter et al (2005). PN AS, 102(3 I). I 1011-1 101 16).

103621 A study on samples from patients with gastric cancer showed the presence of two mutations in PGFR2, Seri67Pro in the lila exon. as well as the 940-2A-G splice site mutation in the lila exon. These mutations were identical to germline activating mutations that cause craniosynostosis syndromes and were observed in 13% of primary gastric cancer tissues studied. In addition, activating mutations in FGFR3 were observed in 5% of tested patient samples, and overexpression of I'GFRs was correlated with poor prognosis in this group of patients (Jang et. al. (2001) Cancer Research 61 3541-3543.

|0363|There are mutations that have been observed in PDGFR in imalinib-treated patients, particularly the T674I mutation. The clinical significance of these mutations may increase significantly, as they currently appear to represent the primary mechanism of resistance to si c A bi inhibitors in patients.

|0364|In addition, there are chromosomal translocations or rare mutations that have been observed in FGFRs that cause gain-of-function, overexpressed, or constitutively active biological signals.

|0365|Compounds according to the invention should therefore find particular application with respect to cancers that express a mimicked molecular target. such as FGFR or PDGFR including PDGFR-beta and PDGFR-alpha. and especially the T674I mutation of PDGFR. Diagnosis of tumors with such hi mutations should be performed using techniques known to those skilled in the art and described herein as R1'PCR and FISI1.

103661 It has been suggested that mutations of the conserved threonine residue on the ATP binding site of FGFR would result in inhibitory resistance. Amino acid valine 561 is mined to ntethionine in FGFRI. corresponding to previously described mutations detected in Abl (1315) and EGFR (1766). which have been shown to transmit resistance to selective inhibitors. Data from the FGFRI V56I M assay showed that this mutation confers resistance to the tyrosine kinase inhibitor compared to the wild type.

Advantages of the compositions according to the invention

|0367|The compounds of formula (I) have several advantages over the compounds of the prior art.

|0368|For example. the compounds of formula (I) have desirable ADMFT and thermochemical properties compared to compounds from the prior art.

Pharmaceutical formulations

|0369| Although it is possible that the active compound is given alone. however, it is preferred that it be in the form of a pharmaceutical composition (eg formulation) containing at least one active compound of the invention together with one or more pharmaceutically acceptable carriers, adjuvants. exeipienasa. thinners, fillers, buffers. stabilizers, preservatives, lubricants. or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.

|0370|Thus, pharmaceutical compositions, as defined above, were further realized by the present invention. and methods for obtaining a pharmaceutical composition containing a mixture of at least one active compound. as What is

defined above. together with one or more pharmaceutically acceptable carriers, excipients. puller. adjuvanas. stabilizers or other materials, as described herein.

(03711 As used herein, then the term "pharmaceutically acceptable" includes compounds, materials, compositions, and/or dosage forms which are.within normal medical judgment.suitable for administration in contact with the tissues of a subject (e.g., the skin) without excessive toxicity, irritation, allergic reaction, or other problem or complication, with a commensurately acceptable reasonable benefit''risk ratio. Any carrier, excipient, etc. must also be "acceptable" in the sense that compatible with other ingredients of the formulation.

J03721Pharmaceutical compositions containing compounds of formula (I) can be formulated using known techniques, see, for example. Remington's Pharmaceutical Sciences. Mack Publishing ("ompanv. Pastors, PA. USA.

(03731 Correspondence. according to the following aspect, the invention has realized the compounds of formula (1) and their subgroups which are defined here in the form of pharmaceutical compositions,

|0374|Pharmaceutical compositions can have any form suitable for oral, parenteral use. local, intranasal, ophthalmic. swelling, rectal. intravaginal. or transdermal application. where the compositions are intended for parenteral administration. they may be formulated for intravenous use. intramuscular. intraperitoneal, subcutaneous administration or for direct delivery to a target organ or tissue by injection, infusion or other routes of administration. Delivery can be by bolus injection, short-term infusion or long-term infusion and can be performed by passive delivery or through the use of an adjustable infusion pump.

|0.375| Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, fillers. bacteriostats. cosolvents, mixtures of organic solvents, cyclodextrin complexing agents, eniulgalore (for the formation and stabilization of emulsion formulations), liposomal components for the formation of liposomes, gelling polymers for the formation of polymer gels, protectants for lyophilization and combinations of agents. among other things, to stabilize the active ingredient in solution and live form and adjust the tonicity of the formulation according to the blood of the target recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous or non-aqueous sterile suspensions that may contain suspending agents and thickening agents (Sirieklv. R.G. (2004). Solubilizing I\ci<p>iens in oral and injectable formulations. Pharmaceutical Research, vol. 21(2). pp. 201-230).

|0376| Liposomes are closed spherical vesicles consisting of outer lipid bilayer membranes and an inner water core and have an overall diameter < 100 pm. Depending on the level of hydrophobicity. moderately hydrophobic drugs can be solubilized by liposomes. if the drug is encapsulated or inserted inside a liposome. Hydrophobic drugs can also be solubilized by liposomes if the drug molecule becomes an integral part of the lipid bilayer membrane, and in this case, the hydrophobic drug is dissolved in the lipid part of the lipid bilayer.

|0377|Formulations can be found in single-dose or multi-dose packages. for example. in hermetically sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid vehicle, e.g., water for injections, immediately prior to use.

|0378| A pharmaceutical formulation may be prepared by lyophilization of a compound of formula (I), or a subgroup thereof. Lyophilization refers to the procedure of drying the composition by freezing. Freeze-drying and lyophilization are therefore used here interchangeably.

|0379| Ex tempore solutions for injections and suspensions can be prepared from sterile vials. granules and tablets.

103801 Pharmaceutical compositions according to the present invention for parenteral injection may also contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable

aqueous and non-aqueous carriers, razrcdivaea. solvents or carriers include water. ethanol. polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose, and suitable mixtures thereof. vegetable oils (such as olive oil), and injectable organic esters. such as ethyl oleate. Adequate fluidity can be maintained, for example. using a coating material such as leeitin. then by maintaining the desired particle size in the case of dispersions, as well as by using surfactants.

(03811 Compositions according to the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of the growth of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents. such as, for example. sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form can be provided by the inclusion of absorption-delaying agents, such as aluminum monostearate.

|0382| In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. application. for example. by injection or infusion. For intravenous administration, the solution may be dosed as such or may be injected into an infusion bag (containing a pharmaceutically acceptable excipient such as 0.9% saline or 5% doxyrose) prior to administration.

[0383] In a further preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

|0384| Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets. pills, lozenges. syrups, solutions, powders. granules, elixirs and suspensions, drying tablets, poultices or plasters and buccal plasters.

|0385| Accordingly. tablet compositions may contain a single dose of the active compound together with an inert diluent or carrier, such as sugar or sugar alcohol, e.g. lactose. sucrose. sorbiol or mannitol; and/or a non-sugar thickener, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or a derivative thereof, such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches, such as corn starch. Tablets may also contain such standard ingredients as binders and granulating agents. such as polyvinylpyrrolidone. disintegrants (eg swelling cross-linked polymers. such as cross-linked carboxymethylcellulose), lubricants (eg stearates). preservatives (eg parabens), antioxidants (eg BI Fl ). buffering agents (eg phosphate or citrate buffers), and effervescent agents such as cytnite bicarbonate mixtures. Such excipients are well known and need not be discussed in detail here.

|0386| Capsule formulations can be of the hard gelatin or soft gelatin type and can contain the active component in a solid, solid or liquid form. Gelatin capsules can be made from animal gelatin or its equivalents obtained synthetically or from plants.

|03871 Solid dosage forms (eg tablets, capsules, etc.) may be coated or uncoated. but they usually have a lining, for example. a protective coating in the form of a film (eg wax or varnish) or a coating for continuous release. The coating (eg Euđragit ™ polymer type) can be designed to release the active ingredient at the desired location within the gastrointestinal tract. Accordingly, the coating may be chosen to degrade under certain pfl conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum or in the duodenum.

103881 In place of the lining or next to it. the drug may be present in a solid matrix containing a controlled release agent, for example. a sustained release agent that may be adapted to selectively release the compound under conditions of moderate acidity or alkalinity in the gastrointestinal tract. Alternativnolome. The matrix material or release delay coating may take the form of an erodible polymer (eg, a polymer of

maleic anhydride) which is essentially contimially eroded as the deionized form passes through the gastrointestinal tract. As a further alternative, the active compound may be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed or sustained release formulations can be prepared according to methods well known to those skilled in the art.

|0389| Pharmaceutical compositions contain from about 1% to about 95%. and preferably from about 20% to about 90%, of the active ingredient. Pharmaceutical compositions according to the invention may be, for example. in the form of a unit dose. such as in the form of ampoules. vial, suppository. dragee. tablet or capsule.

|0390| Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired, by granulating the res.tilting mixture. and by processing the mixture. if desired or necessary, after adding appropriate excipients. into tablets, dragee cores or capsules. It is also possible for them to be embedded in plastic carriers that allow the active ingredients to flow or to be released in measured quantities.

103911 The compounds according to the invention can also be formulated as solid dispersions, ("dispersion types are homogeneous extremely finely dispersed phases of two or more solid substances. Solid solutions (molecular dispersion systems), otherwise one type of solid dispersion, are well known for use in pharmaceutical technology (see (Chiou and Riegelman (1971), J. Pharm. Sci.. 60. 1281-1300) and are useful for increasing rates dissolution and increase in bioavailability of drugs that are poorly soluble in water.

103921 The present invention also provides solid dosage forms containing the solid solution described above. Solid dosage forms include tablets, capsules and chewable tablets. Known excipients can be mixed with the solid solution to obtain the desired dosage form. For example. the capsule may contain a solid solution mixed with (a) a disintegrant and a lubricant. or (b) disintegrant. lubricant and stirfactant tablet may contain a solid solution mixed with at least one disintegrant. lubricant, surfactant and glidant. A chewable tablet may contain a solid solution mixed with a bulking agent. lubricant, and if desired, an additional sweetener (such as an artificial sweetener). and suitable aromas.

|0393| Pharmaceutical formulations may be presented to the patient in "patient packs", i.e. original packs containing therapy for the entire course of treatment in an individual package. usually in the form of blisters. Patient packages have an advantage over traditional prescription drug dispensing. when the pharmacist dispenses to the patient a prescribed amount from a larger package, i.e. a hospital package, because the patient always has access to the patient instructions contained in the patient package, which is normally missing in traditional prescription drugs. Incorporating patient guidance has been shown to improve patient compliance with physician instructions.

103941 Compositions for local application include ointments, creams. sprays, (suppositories, gels, liquid drops and inserts (for example, intraocular inserts). Such compositions can be formulated by well-known methods.

103951 Examples of formulations for rectal or intravaginal administration include pessaries and suppositories which may be. for example, those made of molded, pourable or waxy material. and which contains the active compound.

|()396| Compositions for administration by inhalation may take the form of inhalation powder compositions or medicaments or spray powders and may be administered in standard form using a powder inhalation device or an aerosol delivery device. They knew such devices well. For administration by inhalation, powder formulations usually contain the active compound together with an inert solid powder diluent. like lactose.

|0397|Compounds of formula (I) are generally found in single pharmaceutical form which. as such, it usually contains sufficient compounds to provide the desired level of biological activity. For example, the formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of the active ingredient. Within these limits, specific subranges of compound amounts are from 0.1 milligrams to 2 grams of active ingredient (preferably from 10 milligrams to 1 gram, eg from 50 milligrams to 500 milligrams). or from 1 microgram to 20 milligrams (for example, from 1 microgram to 10 milligrams. e.g. from 0.1 milligram to 2 milligrams of the active ingredient).103981 For oral compositions, the unit dosage form may contain from 1 milligram to 2 grams, and preferably from 10 milligrams to 1 gram, for example, from 50 milligrams to 1 gram. for example from 100 milligrams to 1 gram of active compound.

|0399| The active compound is administered to a patient in need (eg, a human or animal patient) in

the amount that is sufficient to achieve the desired therapeutic effect.

104001 An expert in the appropriate field will use expertise to select appropriate amounts of ingredients for use in formulations. For example, tablets and capsules typically contain 0-20"«) disintegrans, 0-5% lubricants. 0-5% flow-enhancing agents and/or 0-100% fillers or bulking agents (depending on the dosage of the drug). They may also contain 0-10% polymeric binders, 0-5% antioxidants. 0-5% pigments. Slow-release tablets would additionally contain 0-100% polymer (depending on the dose). Tablet or capsule coatings usually contain 0-10% polymer, and/or 0-2% plasticizer.

104011 Parallel formulations usually contain 0-20% buffer. 0-50%) co-solvents, and or 0-100% water for injections (WFI) (depending on dosage and whether they are freeze-dried). Formulations for intramuscular depots may also contain 0-100% oil.

Examples of pharmaceutical formulations

(i) Tablet formulation

|0402|A tablet composition containing a compound of formula (!) was prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as a diluent. and 3 mg of magnesium stearate as a lubricant and was compressed to form tablets in a known manner.

tji) Capsule formulation

104031 A capsule formulation was prepared by mixing 100 mg of a compound of formula (I) with 100 mg of lactose and filling standard opaque hard gelatin capsules with the resulting mixture.

(iii) Injectable formulation I

|0404| A parenteral composition for injection can be prepared by dissolving a compound of formula (I)

(eg in salt form) in water containing 10% propylene glycol to obtain a concentration of the active compound of 1.5% by weight. The solution was then sterilized by filtration, and ampoules were filled with it. which are then closed.

(i\ ) Injectahyl lornnilation 11

104051 The parenteral composition for injection was prepared by dissolving the compound of formula (I) (eg in salt form) (2 mg/ml) and mannitol (50 mg/ml) in water, then sterile filtering the solution and filling into 1 ml resealable vials or ampoules.

(v) Injectable formulation 111

10406|Formulation for i.v. delivery by injection or infusion may be prepared by digesting a compound of formula (I)

(eg in salt form) in water with 20 mg'ml. The vial was then sealed and sterilized by autoclaving.

(vi) Injectable formulation IV

|0407| A formulation for i.v., delivery by injection or infusion may be prepared by dissolving a compound of formula (I)

(eg in salt form) in water containing a buffer (eg 0.2 M acetate pH 4.6) with 2()mg ml. The vial was then sealed and sterilized by autoclaving.

(vii) Formulation for subcutaneous injection

A composition for subcutaneous administration was prepared by mixing the compound of formula (1) with pharmaceutical grade corn oil to obtain a concentration of 5 mg/ml. The composition is sterilized and filled in a suitable container.

(viiil_Liolj!ized

|0409|Aliquots of the formulated compound of formula (I) were filled into 50 ml vials. so they are lyophilized. During thiophilization. compositions were frozen using a one-step freezing protocol at (-45 °C). The temperature was raised to -10°C for curing and then lowered to freezing at -45°C. This was followed by primary drying at -25°C for approximately 5400 minutes, which was followed by secondary drying increasing the temperature to 50°C. The pressure during the primary and secondary drying was set at 80 millitor.

Treatment methods

104101 Compounds of formula (I) and subgroups thereof as defined herein have been found to be useful in the prophylaxis or treatment of a variety of FGFR-mediated diseases or conditions. Examples of such diseases and conditions have already been listed above.

104111 These compounds are generally administered to a subject in need of such administration, e.g. to the patient who is human

or an animal, and it is primarily a human. The compounds are usually administered in amounts that are therapeutically or prophylactically useful and are generally non-toxic.

|04I2|However, in certain situations (for example, in the case of life-threatening diseases), the benefits of administering a compound of formula (I) may outweigh the disadvantages due to toxic effects or side effects. in com

In some cases, it may be considered desirable to administer the compound in amounts associated with a certain degree of toxicity.

|04I3|The compounds may be administered over an extended period to maintain beneficial therapeutic effects or may be administered only for a short period. Alternatively, they can be given intermittently or continuously.

|04I4]A typical daily dose of a compound of formula (I) may be in the range of 100 picograms to 100 milligrams per kilogram of body weight, preferably 5 nanograms to 25 milligrams per kilogram of body weight, preferably 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams. and preferably 1 microgram per kilogram to 20 milligrams per kilogram, for example. of I microgram to 10 milligrams per kilogram) per kilogram of body weight, although higher or lower doses can be given. if necessary. A compound of formula (I) may be administered on a daily basis or on a repeated basis, every 2 or 3 or 4 or 5 or 6 or 7 or 10 or 14 or 21 or 28 days. for example.

|04I5|The compounds of the invention can be administered orally in a range of doses. for example. from 1 to 1500 mg. from 2 to 800 mg. or from 5 to 500 mg, e.g. from 2 to 200 mg or from 10 to 1000 mg, and specific example doses include 10, 20, 50 and 50 mg. The compound may be administered one or more times each day. The compound can be administered continuously (ie, every day without interruption for the duration of the treatment regimen). Alternatively. the compound can be given intermittently. i.e. it can be given continuously for a given period of time, such as Shio is a week. and then stop doing it for a period of time, such as a week. and then give continuously for the next period of time, such as a week, and so on for the duration of the treatment regimen. Examples of treatment regimens involving discontinuous administration include regimens in which administration is administered in cycles of one week on, one week off: or two weeks on, one week off; or Two weeks of taking, one week off: or two weeks of taking, two weeks off: or four weeks of taking, two weeks off: or one week of taking, three weeks off - for one or more cycles, e.g. 2. 3, 4. 5. 6. 7. 8. 9 or 10 or more cycles.

|04I6|According to one preferred dosage schedule, the patient is given an infusion of a compound of formula (I) over a period of one hour per day for up to ten days. and especially up to five days during one week. and the treatment is repeated at the desired interval, such as two or four weeks. and especially every three weeks.

104171 Even more preferably, the patient can be given an infusion of the compound (li) for a period of one hour a day for up to 5 days, and the treatment can be repeated every three weeks.

[04181 According to the following preferred dosing schedule, the patient is given an infusion over 30 minutes to 1 hour. which is followed by maintaining infusions of variable duration, for example from 1 to 5 hours. eg, 3 halls.

1041 *>|According to the following preferred dosing schedule, the patient is given a continuous infusion over a period of 12 hours to 5 days, preferably a continuous infusion of 24 hours to 72 hours

|0420|However, the most preferred amount of compound to administer and the type of composition to be used will be determined at the discretion of the physician based on the nature of the disease or physiological condition being treated.

104211 The compounds delineated herein may be administered as a sole therapeutic agent or may be administered in combination therapy with one or more other compounds to treat a particular condition, for example. neoplastic diseases, such as cancer as defined above. Examples of other therapeutic agents or treatments that can be co-administered (either simultaneously or at different time intervals) with the compounds of formula (I) include the following. but are not limited to:

lopoisomerase 1 inhibitors

antimetabolites

tubulin-targeting agents

DNA binders and lopoisomerase II inhibitors

alkylating agents

monoclonal antibodies

anti-hormones

signal transduction inhibitors

proleasome inhibitors

DNA methyltransferase

cytokines and retinoids

chromatin-targeted therapies

radiotherapy and.

(04221 Other therapeutic or prophylactic agents; for example, agents that reduce or alleviate some of the side effects associated with chemotherapy. Specific examples of such agents include antiemetics and agents that prevent or reduce neutropenia associated with chemotherapy and prevent complications arising from reduced levels of red blood cells or white blood cells, such as. for example, erythropoietin (EPO), granulocyte macrophage colony-stimulating factor (GM-CSF). and Also included are agents that inhibit bone resorption, such as zoledronate and ibandronate, and agents that suppress growth hormone and IGF-1 in patients with acromegaly includes octreotide acetate. which is a long-acting octapeptide with pharmacological properties that mimic those of the natural hormone somatosiatin. Further included are agents such as leucovorin. which is used as an antidote to drugs that reduce levels of lb I ne acid, or folinic acid and agents such as megestrol acetate. which can be used to treat side effects including edema and thromboembolic episodes.

104231 Each of the compounds present in the combinations according to the invention can be administered in an individually adapted dosage schedule and different administration pools.

When the compound of formula (I) is administered in combination therapy with one, two. three, four or more other therapeutic agents (preferably one or two. more preferably one), then the compounds can be administered simultaneously or sequentially. When administered successively, they may be administered at closely spaced intervals (eg, over a 5-10 minute period) or at longer intervals (eg, separated by l. 2. 3. 4 or more hours. or even longer periods, if necessary), with the precise dosing regimen being coordinated with the properties of the therapeutic agent(s).

|0424|The compounds of the invention can also be administered together with nc-chemotherapeutic treatments, such as radiotherapy. Ibtodynamic therapy, gene therapy, surgery and controlled diets.

104251 For use in combined therapy with another chemotherapeutic agent, the compound of formula (1) and one, two. three. four or more other therapeutic agents may. for example. formulate together in a dosage form containing two, three, four or more therapeutic agents. Alternativnolome. the individual therapeutic agents may be formulated separately and may be present together in the form of a set, or kit, optionally with instructions for their use.

104261 One skilled in the relevant art should know within his or her general knowledge what dosage regimens and combinations of therapies to employ.

Diagnostic methods

|0427|Prior to administration of a compound of formula (I), the patient may be examined to determine whether the disease or condition from which the patient suffers or may suffer is one that would respond to treatment with a compound having anti-FGFR activity. VFGFR and or PDGFR.

|0428|For example. a biological sample taken from a patient can be analyzed to determine whether it is sent or diseased. like What is cancer. from which the patient suffers or may suffer, which is characterized by a genetic abnormality or abnormal protein expression that leads to up-regulation of FGFR levels or activity. VEGFR and/or PDGFR or pathway sensitization to normal FGFR. VEGFR and or PDGFR activities, or upregulation of signaling pathways of these growth factors, such as growth factor ligand levels or growth factor ligand activity or upregulation of biochemical pathways downstream of FGFR. VEGFR and or PDGFK activation.

[04291 Examples of such abnormalities resulting from activation or sensitization of FGFR, VEGFR and or PDGFR signaling include loss or inhibition of apoptotic pathways, upregulation of receptors or ligands, or the presence of mutant variants of receptors or ligands, e.g. PTK variants. Tumors with FGFRI mutants. FGFR2 or FGFR3 or FGFR4 or overregulation, especially overexpression of FGFR I. or gain of function mutants of FGFR2 or FGFR3 can be particularly sensitive. sensitive to FGFR inhibitors.

|0430|For example, rare mutations that cause gain of function of FGFR2 have been identified in several conditions (l.emonnier, et al. (2001)..1. Bone Miner. Res.. 16. 832-845). Notably, activating mutations in FGFR2 were identified in 10% of endometrial tumors (Pollock et al, Oncogene. 2007. 26, 7158-7162).

|043l |In addition. genetic aberrations of FGFR3 receptor tyrosine kinase. such as chromosomal translocations or point mutations resulting in ectopically expressed or deregulated. constitutively active FGFR3 receptors. were identified and associated with a subset of multiple myeloma. bladder and cervical cancer (Povvers. C.J., et al. (2000), Endocr. Rel. Cancer, 7. 165). In particular, the "16741 PDGF receptor mutation was identified in imatinib-treated patients.

In addition. demonstrated gene amplification of 8pl2-pl 1.2 in -50% of cases of lobular breast cancer (CLC) and this shows that it is associated with increased expression of FGFR I. Preliminary studies with siRNA. directed against FGFRI, or small molecule receptor inhibitors have shown that cell lines underlying this amplification are particularly sensitive to inhibition of this signaling pathway (Reis-!Tiho et al. (2006) Clin Cancer Res. 12(22): 6652-6662).

|0432|Alternative break. a biological sample taken from the patient can be analyzed for loss of the negative regulator or suppressor of FGFR. VEGFR or PDGFR. In the clinical context, the term "loss" includes the deletion of a gene encoding a regulator or suppressor. truncation of a gene (eg, by mutation), truncation of a transcribed gene product, or inactivation of a transcribed product (eg, by point mutations) or sequestration by another gene product.

104331 The term upregulation includes increased expression or perturbed expression, including gene amplification (ie, multiple copies of a gene) and increased expression by transcriptional effect, and hyperactivity. and activation, including activation by mutations. Accordingly. the patient may undergo a diagnostic test to detect a marker that is characteristic of FGFR overregulation. VEGFR and or PDGFR. The term diagnosis

it also includes screening. By marker we mean genetic markers that include, for example. DNA composition measurement to identify FGFR, VF.GFR and or PDGFR mutations. The term marker also includes markers that are characteristic of FGFR upregulation. VF.GFR and or PDGFR. including enzyme activity, enzyme levels, enzyme state (eg phosphorylated or not) and mRNA levels of the aforementioned proteins.

104341Diagnostic tests and screenings are usually performed on a biological sample selected from tumor biopsy samples, blood samples (isolation and enrichment of taken tumor cells), stool biopsies, sputum. chromosomal analysis, pleural fluid, peritoneal fluid, buccal swabs. biopsies or from urine.

Procedures for identifying and analyzing mutations and protein rearrangements are well known to those skilled in the art. Test procedures may include standard procedures, such as reverse transcriptase polymerase chain reaction (RT-PCR), or in-situ hybridization. such as fluorescence in-situ hybridization or ISU)

(04351Identification of an individual carrying a mutation in FGFR. VEGFR and or PDGFR may mean that the patient would be particularly suitable for treatment with an FGFR, VEGFR and or PDGFR inhibitor. Tumors may be primarily screened for the presence of FGFR. VEGFR and/or PDGFR before treatment. The testing process will usually include direct sequencing. using techniques known to those skilled in the art and described herein, such as RT-PCR and liSI I.

104361 In addition. mutant forms, for example. FGFR or VEGFR2. can be identified by direct sequencing. for example, tumor biopsies using PCR and methods for sequencing PCR products directly as described herein. One of ordinary skill in the art will recognize that all well-known techniques for detecting overexpression, activation, or mutation of the above-mentioned proteins could be applied.

|0437|When testing with RT-PCR. the level of mRNA in a tumor is determined by creating a cDNA copy of the mRNA. followed by cDNA amplification with PCR. PCR amplification procedures. primer selection. and conditions for amplification are known to one skilled in the relevant art. Nucleic acid manipulations and PCR are performed by standard procedures, as described, for example. in Austibel. F.M. el al.. neat. (2004) Current Protocols in Molecular Biology. John Vilev & Sons Inc.. or Innis. VI.A. et-al.. okay. PCR Protocols: a guide to methods and applications. 1990. Academic Press. San Diego. Reaction and manipulation techniques involving nucleic acids are also described in Sambrook et al.. 2001 3rd ed. Molecular Cloning: A l.aboralorv Manual. Cold Spring Harbor Laboratory Press. Alternatively. a commercially available RT-PCR kit (eg, Roche Molecular Biochemicals) or the methodology outlined in US Patents 4,666,828: 4,683,202 can be used; 4,801,531; X192,659, 5,272,057. 5,882,864, and 6,218,529 and which are incorporated herein by reference.

An example of an in-situ hybridization technique for determining mRNA expression would be fluorescence in-situ hybridization (eng. fluorescence in-situ hybridization, abbr. FIS1I) (see Angerer (1987). Metli. Enzvmol.. 152. 649).

104381 In general, in situ hybridization includes the following main steps: and 1) fixation of the tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid, and to reduce non-specific binding; (3) hybridization of the nucleic acid mixture with the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound by hybridization. and (5) detection of hybridized nucleic acid fragments. Probes used in such applications are usually labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides. in order to enable specific hybridization with the target or target nucleic acids under strict conditions. Standard procedures for performing F1SH are described in Ausubel. F.M. et al.. edited. Current Protocols in Molecular

Biologv. 2004. John VIlev & Sons Ine and Pluorescenee In Situ Hvhridizafion: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer. Methods and Protocols. 2nd edition: ISBN: 1 -59259-760-2: March 2004. p. 077-088; Series: Methods in Molecular Medicine.

|0439|Methods for gene expression profiling have already been described (DePrimo et al. (2003). BMC Cancer. 3:3). Briefly, this protocol is as follows: double-stranded cDNA is synthesized from total RNA using (dT)24 oligomers by priming the synthesis of the first strand of cDNA, followed by synthesis of the second strand of cDNA with random hexamer primers. Double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to the protocols described by Affvmeiris (Santa Ciara, CA. USA) and then hybridized overnight on human genome arrays.

104401 Alternatively. protein products that are expressed from mRNA can be determined immunohistochemically from tumor samples, solid phase immunoassays with microtiter plates, and Western blotting. by 2-dimensional electrophoresis on SDS-polyacrylamide gel. with ELISA, flow cytometry and other procedures known from sending techniques for the detection of specific proteins. Detection methods include the use of site specific antibodies. One of ordinary skill in the art will appreciate that all well-known techniques for detecting FGFR upregulation could be applied in the present case. VEGFR and or PDGFR. or FGFR detection. VEGFR and or PDGFR variants or mutants.

|044l|Abnormal levels of proteins such as FGFR or VEGFR can be measured using standard enzyme assays, for example, those assays described herein. Activation or overexpression could also be detected in a tissue sample, for example. tumor tissue. By measuring the activity of lyrosine kinase with a Tesla such as the one from Chemicon International. The tyrosine kinase of interest could be immunoprecipitated from the sample lysates, and then its activity could be measured

[04421Alternative methods of measuring the overexpression or activation of FGFR or VEGFR including their isoforms include measuring the density of microvessels. She can. for example. measured by the method described by Orre and Rogers (Ini .1 Cancer (1999), 84(2) 101-8). Testing methods also include the application of markers, for example. in the case of VEGFR they include CD3I. C D3 I and CDIOŠ (Miueo et al. (2004).1 Clin Pathol. 57(6). 591-7).

|0443|Therefore, all these techniques could also be applied to identify tumors, especially those that are amenable to treatment with compounds according to the invention.

[0444] The compounds of the invention are particularly useful in the treatment of a patient having an FGFR mimic. The G697C mutation in FGFR3 is observed in 62% of oral squamous cell carcinomas and causes constitutive activation of the kinase activity. Activating FGFR3 mutations have also been identified in bladder cancer cases. There were 6 types of these mutations, with varying degrees of prevalence: R248C. S249C. G372C, S373C, V375C, K6520- Next to the logo. it was determined that the Gly388Arg polymorphism in FGFR4 is associated with an increased incidence and aggressiveness of prostate and colon cancer. lungs and breasts.

Therefore, a further aspect of the invention includes the use of a compound according to the invention for the manufacture of a drug for the treatment or prophylaxis of a disease or condition in a patient who has been screened to determine whether the disease or condition from which the patient suffers or may suffer is one that would respond to treatment with a compound having anti-FGFR activity.

104461 Specific mutations for which a patient is screened include G697C. R248C. S249C. G372C. S373C, Y375C. K652Q mutations in FGFR3 and Gly388Arg polymortism in FGFR4.

|0447|According to the following aspect of the invention, the compounds according to the invention are covered if they are used for the prophylaxis or treatment of cancer in a patient selected from a subpopulation possessing a variant of the FGFR gene (eg. G697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

|0448|MRI determination of vessel normalization (eg using MRI gradient echo. spin echo. and contrast enhancement to measure blood volume. relative vessel size and vasculature permeability) in combination with circulating bioinarkers (circulating progenitor cells (CPCs). C'F.Cs. SOFI. and PCj 1-2) can also be used to identify VEGFR2-resistant tumors for treatment with compound according to the invention.

General synthesis procedures

Description of the aiialiiic. LC-MS systems and methods

10449) In the experiments, the obtained compounds were characterized by liquid chromatography and mass spectroscopy using commercially available systems (VWaters Plalform LC-MS system. Vwaters Fractionlynx LC-MS system), standard operating conditions and commercially available columns (Phenomene.v. Waters, etc.). but an expert in the relevant field will consider alternative systems and methods that could be used. When atoms with different isotopes are present and only one mass is given. then the mass given for the compound is the monoisotopic mass (ie "Cl; 7"F3r etc.).

Mass-controlled purification of LC-MS systems

|0450|Preparative LC-MS (or HPLC) is a standard and efficient method used for the purification of small organic molecules, such as the compounds described herein. Liquid chromatography (LC) and mass spectrometry (MS) methods can be varied to provide better separation of crude materials and improved detection of samples with MS. Optimization of the preparative gradient LC method will include varying columns, volatile eluents and modifiers. as well as gradients. Methods for the optimization of preparative and non-LC-MS methods, as well as for their use in the purification of compounds, are well known in the relevant field. Such methods are described in Rosentreter U, l-luber U.; Optimal fraction collecting in preparative LC MS: .1 Cornh Chem.: 2004: 6(2). 159-64 and Leister W. Stratiss K. Wisnoski D, Zhao Z. Lindslev C., Development of a custom high-throughput preparative liquid chromatograph/mass spectrometer platform for the preparative purification and analvtical analysis of compound libraries: .1 CombGhem.; 2003: 5(3): 322-9.

|045! Two such preparative and vnom LC-MS compound purification systems are the Waters Lr;icionlynx system or the Agilent 1 100 LC-MS preparative system, although one skilled in the relevant art will appreciate that alternative systems and methods could be used. For the compounds described here, reversed-phase preparative and vnu HPLC methods were particularly used, but methods based on normal-phase preparative LC could be used instead of reversed-phase methods. Most preparative LC-MS systems use reversed-phase LC and volatile acid modifiers. because this approach is very efficient for the purification of small molecules and because the eluents are compatible with positive-ion electrospray mass spectrometry. The most suitable type of preparative chromatography is chosen according to the obtained analytical trace. A typical routine is to perform analytical LC-MS using the type of chromatography (low or high pH) most suitable for the structure of the compound. When the analytical trace shows good chromatography. then a suitable preparatory method of the same type is chosen. For the purification of compounds bi

a number of other chromatographic solutions could be used, e.g. normal or reverse phase LC; acidic, basic, polar or hydrophilic buffered mobile phases; base modifiers could be used to purify compounds. Based on the information obtained, one skilled in the art would be able to purify the compounds described herein using preparative LC-MS.

|0452|All compounds were typically dissolved in 100% MeOH or 100% DMSO.

Main road A

|0453|

Procedure AI -.tbrinjranje:iniid.azopyridinskij.pi;sleny 104541

|0455|To a solution of methyl 2-aminopyridine-4-carboxylate (10.0 g. 66 mmol. 1.0 equiv) in EtOH (150 mL) was added Nal lCCh(ILI g. 132 mmol, 2.0 equiv), which was followed by chloroacetaldehyde (50 wt % in water, 13.0 mL. 99 mmol. 1.5 equiv). The mixture was refluxed for 2 h. The solvents were removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The drying precipitate was washed with Ef.O and then recrystallized from MeOH/Et.OH to give 8.4 g of product. 1 H NMR (400 MHz. DMSO-d6): 8.66 (1II, d), 8.16 (2H, s). 7.80 (IH. s), 7.33 (II I. d). 3.90 (3H, s). MS; | M • 111 177.

Prpe eđura A 2 - hi dro 1 and for estra

]0456|

|0457|To a solution of methyl imiclazo[1.2-a]pyridin-7-carboxylate (3.0g. 17.(W mmol. 1.0 equiv) in F.tOH (150 ml) was added 2M aqueous KOM (85 ml. 170 mmol. 10 equiv). The solution was heated for 50 min at 60'C. After cooling to room temperature, the reaction was neutralized. (HCl), and the solvents were removed under reduced pressure. The residue was stirred in EtOH (2 x 100 ml), and the solvent was removed under reduced pressure, and the resulting product was used in the next step without further purification by MS:

Procedure ^

|0458|

[0459|To a solution of imidiazo 1,2-a]pyridine-7-carboxylic acid (1.0 equiv) in DMF1EO (50:1) was added TBTU (1.5 equiv) and FIOBT (1.5 equiv). The reaction was stirred at room temperature for 30 min before amine (2.0 equiv) was added. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was poured onto an SCX cartridge and washed with MeOH (2 column volumes) before the product was eluted with methanolic ammonia (2 column volumes). Raslvarać was removed under reduced pressure and. if necessary, the product was purified by chromatography on silica (0 » 50% MeOH Et >0). Procedure A I - iodination104601

|046l |To a solution of imidazo 1,2-pyridine-7-carboxylic acid amide (1.0 equiv) in DMF (280 ml) was added N-iodosuccinimide (1.2 equiv), and the resulting mixture was stirred for 2 h at room temperature. It was a rare brown sludge

diluted with water. 10%w/v sodium lyosulfate and sodium carbonate (1 M) and then extracted with 1-tOAc. The aqueous was further extracted with EtOAc. The combined organic phases were washed with brine (280 mL), then dried (MgSO 4 ) and concentrated with iodine to give a brown residue. The rest was triturated with ether. then it was filtered and the solid was washed with ether (2 x 5()ml) and dried on lllter to give the product. If necessary, the product was purified by chromatography on silica (0 » 50% MeOH·Et·O).

Procedure A5b Suzuki coupling with the pinacol ester of 1-([1,3.4Jliadiazol-2-ylamiiK)J-phenyl !>o:ous acid 104621 104631 Solution of 7-amid o-3-j of o-imidazo[1.2-a]pyridin a (1 equiv) in DM l. 3-([1,3.4]thiadiazol-2-ylamino)-phenyl boronic acid pinacol ester (1.2 equiv) were added. I M Na-CO-, (8 equiv) |reaction was degassed by bubbling N-, through it], which was followed by tetrakis(triphenylphoslin)palladium ions(0) (0.05 equiv). The mixture was heated at 80°C overnight. and then diluted with water and extracted with F.tOAc. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure. The products were purified by trituration with Et.O or column chromatography on silica (0 »50% VleOI! I .:<)'.

(»pst and path B

10464]

Procedure BI - amide and mi dazo[ 1,2-a]pyridin-7-carboxylnecIse I ine(0465|

(04661Obtained using general route A of procedure Al. replacing 2-aminoisonicotinamide with methyl 2-aminopyridine-4-carboxylate. 1H NMR (400 MHz, DMSO-d6): 8.59 (IH. d). 8.16 (IH. si, 8.13 (III, s), 8.05 (III. S). 7.71 (I H, s). 7.52 (I H. s). 7.32 (II I. dd). MS: [M + H] 162.

Procedure B2 - amide of 3-iodoimidazo[1,2-aJpyridine-7-carboxylic acid

104671

10468]Obtained using General Path A procedure A4. with the replacement of the imidazo[l.2-a]pyridine-7-carboxylic acid amide with methyl imidazo[l.2-a]pyridine-7-carboxylate. 1 H NMR (400 MHz. DMSO-d 6 ): 8.39 (1 H. d). 8.25-8.09 (3H, m), 7.86 (1H, s), 7.56-7.45 (1H, dd). MS: |M i i I] 288. Procedure B3 - Suzuki, entry 104691

3-Iodoimidazo[1,2-a|pyridine-7-carboxylic acid amide was coupled as described in general route A. procedure A5.

104701

EXAMPLES AND DO4

|04711 Following the methods described above, compounds from Examples I to 4 were obtained

which are listed in the table below.

Biological tests

FGFR.3 and PDGFR//; viirotests of inhibitory activity of kin/e

|04721 Enzymes (Upstate) were prepared at 2\final concentration in 1x kinase assay buffer (as described below). The enzymes were then incubated with the test compound. with biotinylated Flt3 substrate (biotin -DNEYf YV) (Cell Signaling Technologv Inc.) and ATP. The reaction was allowed to proceed for 3 h (FGFR3) or 2.5 h (PDGFR-beta) at room temperature on a plate shaker at 900 rpm before being stopped with 20 µl of 35 mM EDTA. pH 8 (FGFR3) or 55 mM EDTA. pi t 8 (PDGFR-beta). Twenty ml of 5x detection medium (50mM HEPES pll 7.5. 0.1% BSA. 2nM Eu-anti-pY (PY20) (PerkinEImer) 15nM SA-XL665 (Cisbio) for FGFR3 and 50mM HEPES, pH 7.5. 0.5M KF. 0.1% BSA. 11.54nM were then added. Eu-anti-pY (PT66)

(PerkinEImer). 94nM SA-XL665 (Cisbio) for PDGFR-beta) was then added to each well, and the plate was hermetically sealed and incubated at room temperature for one hour on a plate shaker at 900 rpm. The plate was then read on a Packard Fusion plate reader in TRF mode.

|0473| Kinase assay buffers were:

A: 50 mM HEPES pH 7.5. 6 mM MnCK. 1 mM DTT, 0.1%, TritonX-100

B: 20 mM MOPS pl l 7.0. 10 mM MnCE, 0.01% Triton X-100. I mM D l T. 0.1 mM sodium orthovanadate

|0474|Compounds according to the invention have IC50 values of less than 10 µM or provide at least 50% inhibition of FGFR3 activity at a concentration of 10 µM. Preferred compounds of the invention (eg, Examples 1-4) have IC50 values of less than 1 pM in the FGFR3 assay.

VI-GI R2! n virotest of inhibitory kinase activity

10475|Tested reactions containing VEGFR2 enzyme (obtained from Upstate). and 250 µM Poly(Glu.Tvr) 4:1 substrate (CisBio) in 50 mM HEPES, pH 7.5, 6 mM Mn(12.1 mM DTT, 0.01% TritonX-100, 5 µM ATP (2.8 Ci/mniol) were prepared in the presence of compound. Reactions were stopped after 15 min by addition of excess phosphoric acid. The reaction mixture was then transferred to Millipore MAPH litter plate where the peptides are bound, while the unused ATP is washed away.After washing, the scintillation agent is added, and the incorporated activity is measured by scintillation counting on a Packard 1 opcotint.

FGFRI, FGFR2, FGFR4, VEGFRI and VEGFR3 //; viiro assays for kinase inhibitory activity

|0476| Inhibitory activity against FGFRI. FGFR2. FGFR4. V FGFR I and VEGFR3 can be determined from Upstate Discover Ltd. Enzymes were prepared at 10x final concentration in the enzyme pathway (20 mM MOI'S. pll 7.0. 1 mM EDTA. 0.1% B-mercaptoethanol. 0.01% Brij-35, 5% glycerol. 1 mg/ml BSA). Enzymes were then incubated in assay puter with various substrates and "P-ATP (-500 epm/pmol) as described in the table.

104771 The reaction was initiated by the addition of Mg ATP. The reaction was allowed to proceed for 40 minutes at room temperature before being quenched with 5 in 1 3% phosphoric acid solution. Ten ml of the reaction mixture was transferred to either a tiltermatA or a P30 filtermat and then washed three times in 75 mM phosphoric acid and once in methanol before being dried for scintillation counting.

[0478] Compounds were tested at the concentrations listed below in duplicate against all kinases. and then the percentage activity compared to the control was calculated. Where inhibition was high, IC<S>1, was determined.

Enzyme buffer A: 8 mM MOPS, pFI 7.0. 0.2 mM EDTA. 10 mM MgAcetate

Enzyme buffer B: 8 mM MOPS, pll 7.0. 0.2 mM EDTA, 2.5 mM MnCl2. 10 mM MgAcetate

Enzyme buffer C: 8 mM Mops. pH 7.0. 0.2 mM EDTA. 10 mM MnCl2, 10 mM MgAcetate.

Cell-based pFRK ELISA assay

104791LP-1 or JIM-I multiple myeloma cells were seeded in 96-well plates at 1 x 10 cells/ml at 200 µl per well in serum-free medium. FIUVEC cells were seeded at 2.5 x (F cells/ml) and allowed to recover for 24 h before being transferred to serum-free medium. The cells were incubated for 16 h at 37 "C before the addition of the test compound for 30 min. The test compounds were administered at 0.1% final DMSO concentration. After this 30-min incubation, the FGF-I mixture was added to each well. Ileparin (FGF-I with lOOng/ml final and Heparin with lOOug/ml) or VECiF"'1 (1 00ug ml) for the next 5 minutes, the medium was removed, and 50ul of ERK ELISA lysis buffer was added (R and D Systems DuoSet ELISA for pFRK and Total ERK '?DYC-I940E, DYC-I0I8E). ELISA plates and standards were prepared according to standard DuoSet protocols, and the relative amounts of pERK acc total ERK in each sample were calculated based on the standard curve.

|()480| The compounds according to the invention were tested in particular against the 1.P-1 cell line (DSMZ bi.: ACC 41) obtained from human multiple myeloma. Many compounds of the invention were found to have IC50 values of less than 20 µM in this assay, and some compounds (eg, Example 2) had IC50 values of less than 1 µM.

Testo vjhse lekt i v nos ti ba^jra n i n a H U V EC jć^ljjania

104811HUVEC cells were seeded in 6-well plates and 1 x 1 ()" cell well. then allowed to recover for 24h. They were transferred to serum-free medium 16 hours before treatment with the tested compound for 30 minutes in 0.1% final DMSO concentration. After compound incubation, EGF-I (l()0ng/ml) and l leparin were added (100ug/ml) or VEGF (100ng/ml) for 5 minutes. The medium was removed and the cells were washed with ice-cold PBS. so they were lysed in lOOul TG lysis buffer (20mM I ris. E30nM NaCl. 1% Eriton-X-100. 10% glycerol. protease and phosphatase inhibitors. pll 7.5). Samples containing equivalent amounts of protein were prepared with LDS sample buffer and run on SDS PAGE. which was followed with western blotting for multiple downstream targets of the VEGFR and FGFR pathways including phospho-FGFR3, phospho-VEGFR2 and phospho-ERKI 2.

//' l'j' ?'mode 1 jjhjpjerten zije

104821 There are several animal models for measuring the potential hyperlensic effects of small molecule inhibitors. They can be classified into two main types: indirect and direct measurements. The most common indirect method is the cuff technique. Such methods have advantages because they are noninvasive and as such can be applied to a larger group of experimental animals, however, this process allows for occasional, that is, discrete sampling of blood pressure and requires the animal to be restrained in some way. The use of a restraining agent can lead to stress in the animal, which means that changes in blood pressure that can be attributed to the specific effect of the drug are difficult to observe.

|0483| Direct methodologies include those using radio telemetry technology or implanted catheters connected to externally mounted transmitters. Such methods require a high level of technical expertise for the initial surgery that is included yesterday in the implantation, and the costs associated with it are high. However, the key advantage is that they allow continuous monitoring of blood pressure without. restraints during the time period of the experiment. An overview of these methods can be found in Kurz et al (2005) Uvpertension. 45: 299-310.

hERG activity

|0484| The activity of compounds of formula (I) against the hERG K ion channel can be determined using the test described in the article by M. I. Bridgland-Tavlor et al.. Journal of Pharmacological and 1 o\icological Methods, 54

(2006). 189-199. This lonWorksIM Hi hERG screening test is performed commercially by Upstate (Millipore) using the PrecislON™ hERG-CHO cell line.

Determination of potency against cytochrome P450

104851 Potency of compounds of formula (I) against cytochrome P450 (CVP450) enzyme IA2. 2C9. 2CI9, 3A4 and 2D6 can be determined using Pan Vera Vivid CYP450 screening kits available from Invitrogen (Paislev, UK). CYP450s are delivered as baculosomes containing CYP450 and NADPH reductase, and the substrates used are fluorescent Vivid substrates. The final reaction mixtures were as follows:

IA2

100 mM potassium phosphate. pH 8. 1% acetonitrile. 2 in IVI IA2 Rlue vivid substrate. 100 µM NADP'. -I nM CYP450 IA2. 2.66 mM glucose-6-phosphate. 0.32 U mi glucose-6-phosphate dehydrogenase.

2C9

50 mM potassium phosphate, pH 8. 1% acetonitrile. 2 uM Green vivid substrate. 100 µM NADP. 8 nM CVP450 2C°, 2.66 mM glucose-6-phosphate, 0.32 U/ml glucose-6-phosphate dehydrogenase. 2C19 50 mM potassium phosphate, pH 8. 1% acetonitrile. 8 uM Blue vivid substrate. 100 µM NADP, 4 nM CYP450 2C19 2.66 mM glucose-6-phosphate. 0.32 U/ml glucose-6-phosphate dehydrogenase.

3A4

100 mM potassium phosphate, pH 8, 1% acetonitrile. 10 uM 3A4 Blue vivid substrate. 100 µM NADP'. 2.5 nM CYP450 3A4, 2.66 mM glucose-6-phosphate, 0.32 U/ml gluco/α-6-phosphate dehydrogenase.

2D6

100 mM potassium phosphate, pH 8. 1% acetonitrile, 5 µM 2D6 Blue vivid substrate. 100 µM NADP. 16 nM CYP450 2D6, 2.66 mM glucose-6-phosphate, 0.32 U/ml glucose-6-phosphate dehydrogenase.

10486] Fluorescence was monitored for 20 minutes at 30 second intervals on a Molecular Devices Gemini fluorescence plate reader. Excitation and emission wavelengths were 390 nm and 460 nm for IA2. 2CI9 and 3A4, 390 nm and 485 nm for 2D6 and 485 nm and 530 nm for 2C9. The initial values are determined from the progress curves.

[0487] The test compound was prepared in methanol or acetonitrile. so it was tested against CYP450s at a concentration of 10 uM.

Ba/F3-TEE-FGFR3 & Ba/F3 (VVTjcell) Proliferation Assays

10488|Stably transfected Ba/F3-TEL-FGFR3 cells were seeded in black clear-bottom 96-well tissue culture plates in RPMI medium containing 10% FBS and 0.25 mg'ml G4 I 8 at a density of 5 x 10' cells/well (200 µl per well). Parental wild-type Ba F3 cells (DSMZ no.: ACC 300) were seeded in black 96-well clear-bottomed tissue culture plates in RPMI medium containing 10% FBS and 2 ng/ml mouse IL-3 (R&D Sysems) at a density of 2.5 x 10' cells per well (200 uI per well). Plates were incubated overnight before addition of compounds the following day. Compound dilutions were made in DMSO starting at 10 mM and diluted in wells to give a final DMSO concentration of 0.1% in the assay. Compounds were left on the cells for 72 hours before the plates were removed from the incubator, and 20 µl Alamar Blue™ (Biosonrce) was added to each well. Plates were incubated for 4-6 hours before reading the plates at 535 nm (excitation) • 590 nm (emission) on a Fusion plate reader (Packard).

|0489] Many compounds of the invention are expected to be more active against the Ba F3-TEL-FGFR3 cell line than against the wild-type parental Ba/F3 cell line. for example. more than 5-fold, and especially to be more than 10-fold more active against the Ba/F3-TE1 -FGFR3 cell line than against the wild-type parental Ba/F3 cell line.

Claims (12)

1. Compound of formula (I): where —<:->represents a single or double bond. easily gives at least one bond in a 5-membered ring system a double bond: ring A may be optionally substituted with 1. ?. or 3 R'' groups; B represents a -heterocyclyl group where said heterocyclyl group may be optionally substituted with I. 2 or 3 R<a>groups; R" represents halogen. C1-6 alkyl, C2-6 alkenyl, C1-6 alkynyl. C3-6 cycloalkyl. C 1 -cycloalkenyl. -OR\ -O-(CH?>,rOR\ haloC,.,, alkyl, haloC,.,, alkoxy. C,.„ alkanol, =0. =S. nitro, Si(R")4. -(CH.).-CN, -S-R\ -SO-R\ -SOrR\ -COR\ -<CR'R" )r COOR'. -(CHA-CONR<x>R\ -(CH.),-NRXR\ -(CH,k-NlOCOR<?>. iClLi -M^SO -R\ - (CH,),-NH-S02-NRvR\ -OCONRxR\ -(CH>)„-NRTO.R1 .-(>-( CI 1 >),CR"R>-(CH-),-OR') or -(CH])s-SO,NR''R<>> groups; R\ R<y> and R' independently represent hydrogen. CM, alkyl. C\<, alkenyl. C. „ alkynyl, CM, alkanol. hydroxy. C,.„ alkoksi, haloC,.,.alkil. -CO-(CH>)„-€,.„ alkoksi. C\.scikloalkil ili Ci.scikloalkenil; R 7 and R 5 independently represent hydrogen. CM, alkyl. C:.„ alkenyl. C: „ alkynyl, C;.cycloalkyl, C;.cycloalkenyl, aryl, heterocyclyl or R and R<s> together with the nitrogen atom to which they are attached may form a heterocyclyl ring containing nitrogen. wherein said CY(, alkyl. aryl and heterocyclyl may be optionally substituted with 1, 2 or 3 R groups; R' and R" independently represent the R<:>' group or -V-carbocyclic or Z heterocyclyl group, wherein said carbocyclic and heterocyclyl groups may be optionally substituted with 1, 2 or 3 R' groups: Y and Z independently represent a bond. -rO-(CH,),-, -COO-. -(CN,),,-. -NR<X->(CH?)S-. -(CH:],-NRY -CONRV - NR<v>CO-, -SO,NR\ -NR-SO,-. -NRvCONR\ -NRXCSNR>-, ■ 0-(CM.),-. -(CHA-0-. -S-. -SO- or -<CH,)5-SOr; n represents an integer from 1-4: s and t independently represent an integer from 0-4: q represents an integer from 0-2: or a pharmaceutically acceptable salt or solvate thereof. 2. The compound according to claim I. wherein B represents an aromatic or non-aromatic heterocyclyl group: R" represents halogen. Cu. alkyl. C..„ alkenyl. C.-.,, alkynyl. ('"•„„ cycloalkyl, C;.s cycloalkenyl. -OR\ -O-(CH>)„-OR\ haloC,,, alkyl. haloC,.,. alkoxy. C,„ alkanol. O. S. niiro.-(ClhivCN. -S-R\ -SO-R\ -SO<-R\-COR\ -(CRVR-VCOOR'. -(CH;,)s-CONR'R;. -(Cl f.)s-NRvR\ -(CH.)„-N<R>vCO<R>\ -(C>l,^-NRxSO;>-R\ -OCON-RxR-*. - (CH^-NRVO^. -0-(Cl I .»,CRxR'-(CI-|,),-OR' or -(CH.»,-SGsNR<x>R<l>groups: Y and Z independently represent a bond. -CO-. Cl l:-. -(CTC)--. ;C!I ).. - OK II >.. or -Ml-U ll 3. A compound defined according to claim 2 wherein the heterocyclyl group is a shift member monocyclic heterocyclyl group. 4. A compound defined according to claim 3, wherein the heterocyclyl group is pyridyl, pyrazinyl. triazolyl. oxadiazolyl, imidazolyl or thiadiazolyl. 5. A compound defined according to claim 4 wherein the heterocyclyl group is thiadiazolyl. 6. A compound delineated according to any of the preceding claims wherein q represents 0. 7. A compound defined according to any of the preceding claims wherein R and R<*> together represent hydrogen or Cu, alkyl; or one of R and R* is hydrogen and the other is C 1 -alkyl (optionally substituted with an -ORx group), C 1 -cycloalkyl or heterocyclyl. 8. A compound defined according to any of the preceding claims I - 6, wherein R and Rk together with the nitrogen atom to which they are attached form a heterocyclyl ring optionally substituted with I, 2 or 3 R1' groups. 9. A compound as defined in any of the preceding claims having the following ring system: 10. a pharmaceutical composition containing a compound of formula (I) defined according to any of claims I to 9. 11. A compound defined according to any one of claims 1 to 9 for use in therapy. 12. A compound defined according to any one of claims I to 9 for use in the prophylaxis or treatment of cancer.